BIOPHARMACEUTICS

AND
CLINICAL PHARMACOKINETICS (Phar4151)

By
Balisa Mosisa
(B.Pharm, M.Pharm, PhD Fellow,
Assistant Professor of Pharmaceutics)
 Course Syllabus
Course Description: The course deals with:
 Mechanisms of drug ADME,
 Effect of our body on drugs ADME,

 Effect of physicochemical properties of the drug on ADME,

 Effect of dosage forms on ADME,
 Bioavailability and bioequivalence, and

 How to monitor and control drugs in the body

1. Introduction to biological system (2hrs)
 Biopharmaceutics is the study of the chemical and physical
properties of drugs and the biological effects they produce.
 It is a major branch in pharmaceutical sciences which relates
between the physicochemical properties of a drug in dosage
form and the pharmacology, toxicology, or clinical response
observed after its administration.
 It is related to the onset, duration, and intensity of drug
action.
 It examines the interrelationship of the physicochemical
properties of the drug, the dosage form in which the drug is
given, and the route of administration on the rate and extent of
systemic drug absorption.
Thus, biopharmaceutics involves factors that influence
(1) The stability of the drug within the drug product,

(2) The release of the drug from the drug product,

(3) The rate of dissolution/release of the drug at the
absorption site, and
(4) The systemic absorption of the drug.
 The study of biopharmaceutics is based on fundamental
scientific principles and experimental methodology.
 Studies in biopharmaceutics use both in-vitro and in-vivo
methods.
 In-vitro methods are procedures employing test apparatus and
equipment without involving laboratory animals or humans.
 In-vivo methods are more complex studies involving human
subjects or laboratory animals.
 These methods must be able to assess the impact of the
physical and chemical properties of the drug, drug stability, and
large-scale production of the drug and drug product on the
biological performance of the drug.
Pharmacokinetics is a science dealing with how drugs reach
their site of action and are removed from the body.
 Pharmacokinetics is concerned with the accurate determination
of the magnitude of the independent variable in pharmacology
and therapeutics, namely, the concentration of drug in the
body at the biological target of interest.
 The following processes govern the rate of accumulation and
removal of drug from an organism-absorption, distribution,
metabolism, and excretion.
 ADME processes affect not only the rate of accumulation of a
drug at its site action, but also its rate of removal.
 It predicts drug concentrations at the target site over time.
 Pharmacokinetic principles integrate drug ADME.
Clinical pharmacokinetics provides a quantitative description
in humans of the behavior of drugs with different
characteristics as well as the differences expected from
different routes of drug administration.
• Drug administration–Drugs can enter the body from several
sites, with the route of administration having a significant
influence on the ability of a drug to accumulate at its site of
action.
Drug Absorption: is the process of a substance entering the
body.
 Drugs can be absorbed into the circulation from numerous sites
within the body.
• Absorption is the assimilation of the drug from the GIT into the
bloodstream or the lymphatic system.
• Molecules of drug must pass through the various complex
membranes made of lipid barriers, and various mechanisms
may be involved in the process of absorption.
• The following stages must be considered: Dissolution of the
drug into the membrane material; Transcellular passive
diffusion through the membrane, or even active transport ;
Luminal and epithelial metabolism
Drug Distribution: is the dispersion of s/bs throughout the
fluids and tissues of the body.
 It is the movement of a drug to and from the blood and various
tissues of the body (for example, fat, muscle, and brain tissue) and
the relative proportions of drug in the tissues.
 Once in the circulation, the drug is transferred to the
interstitial fluid and to the cells of the body.
 Distribution is a term indicating the way in which the unbound
drug in the blood passes into the tissues or organs.
 The drug molecule leaves the intravascular compartment to be
redistributed between extracellular and intracellular
compartments, and reaches the receptors lying in the tissues.
Drug Metabolism:  is the term used to describe the
biotransformation of pharmaceutical substances in the body
so that they can be eliminated more easily.
 The majority of metabolic processes that involve drugs occur
in the liver, as the enzymes that facilitate the reactions are
concentrated there
 It is the irreversible transformation of parent cpds into
daughter metabolites.
 The drug is inactivated by various processes, based on
chemical alteration of the molecule with metabolism, and
excretion via various organs.
 Metabolism is biotransformation of endogenous and
exogenous substances that occur in the living cells.
 The metabolites formed from a drug during its
biotransformation are generally more water-soluble than the
drug itself, facilitating their excretion through the urine.
 There is an increased interest in the chemical changes in a
drug once it enters the body.
 In most cases, these drug biotransformation reactions
produce intermediates with less pharmacologic activity than
the parent compound; however, some drug metabolites
possess significant pharmacologic action.
 Furthermore, some metabolites are chemically reactive and
capable of contributing to toxicity, mutagenesis,
carcinogenesis, and birth defects.
 Most drugs must pass through the liver, which is the primary site
for drug metabolism.
 Once in the liver, enzymes convert prodrugs to active metabolites
or convert active drugs to inactive forms.
Drug Excretion: is the elimination of the substances from the
body.
• Excretion involves elimination of the drug from the body, for
example, in the urine or bile.
• Excretion of the drug and its metabolites from the organism
is primarily undertaken through the kidney and the intestinal
tract; only gaseous substances (anesthetics) are excreted
via the lungs.
• The primary sites for drug excretion are the liver and kidney,
although the skin, lungs, and bile and intestine may be sites
for excretion as well.
• The rate and extent of renal excretion is determined by
glomerular filtration, tubular reabsorption, and tubular
secretion.
1.1. GIT Physiology
 The GIT extends from the mouth to the anus.
 It consists of the oral cavity, pharynx, esophagus, stomach, small
intestine, and large intestine.
 Most dugs and food absorption take place in the small intestine.
 Undigestible material is eliminated by the large intestine (also
called the colon).
 The accessory organs of GIT are the teeth, tongue, salivary
glands, liver, gallbladder, and pancreas.
 Digestion and absorption does not take place within these
organs, but each contributes something to the digestive and
absorption process.
STOMACH
• Stomach is a sac that extends from the esophagus to the small
intestine.
• It is a reservoir for food, so that digestion proceeds gradually.
• Both mechanical and chemical digestion take place in the
stomach

The stomach
 The fundus and body are mainly storage areas, whereas most
digestion takes place in the pylorus.
 The gastric pits are the glands of the stomach and consist of several
types of cells; their collective secretions are called gastric juice.
 Mucous cells secrete mucus, which coats the stomach lining and helps
prevent erosion by the gastric juice.
 Chief cells secrete pepsinogen, an inactive form of the enzyme pepsin.
 Parietal cells produce hydrochloric acid (HCl); these cells have
enzymes called proton pumps, which secrete H+ ions into the
stomach cavity.
 The H+ ions unite with Cl– ions that have diffused from the parietal
cells to form HCl in the lumen of the stomach.
 HCl converts pepsinogen to pepsin, which then begins the digestion of
proteins to polypeptides, and also gives gastric juice its pH of 1 to 2.
 This very acidic pH is necessary for pepsin to function and also kills
most microorganisms that enter the stomach.
 The parietal cells also secrete intrinsic factor, which is necessary for
the absorption of vitamin B12.
 Enteroendocrine cells called G cells secrete the hormone gastrin, a
hormone that stimulates the secretion
 of greater amounts of gastric juice.

 Gastric juice is secreted in small amounts at the sight or smell of

food.
 Stimulatory impulses are carried from the CNS by the vagus nerves
(10th cranial) and provide for very efficient mechanical digestion to
change food into a thick liquid called chyme.
 The pyloric sphincter is usually contracted when the stomach is
churning food; it relaxes at intervals to permit small amounts of
chyme to pass into the duodenum.
 This sphincter then contracts again to prevent the backup of intestinal
contents into the stomach
SMALL INTESTINE
• The small intestine is about 2.5 cm in diameter and
approximately 6m long and extends from the stomach to the
cecum of the large intestine.
• The duodenum is the first 25 cm of the small intestine.
• The common bile duct enters the duodenum at the ampulla of
Vater (or hepatopancreatic ampulla).
• The jejunum is about 8 feet long, and the ileum is about 11 feet
in length.
• In a living person, however, the small intestine is always
contracted and is therefore somewhat shorter.
• Digestion is completed in the small intestine, and the end
products of digestion are absorbed into the blood and lymph.
• The mucosa (see Fig. 16–4) has simple columnar epithelium that
includes cells with microvilli and goblet cells that secrete mucus.
• Enteroendocrine cells secrete the hormones of the small intestine.
 Lymph nodules called Peyer’s patches are especially
abundant in the ileum to destroy absorbed pathogens.
 The external muscle layer has the typical circular and
longitudinal smooth muscle layers that mix the chyme with
digestive secretions and propel the chyme toward the colon.
 Stimulatory impulses to the enteric nerves of these muscle
layers are carried by the vagus nerves.
 The waves of peristalsis, however, can take place without
stimulation by the central nervous system; the enteric
nervous system can function independently and promote
normal peristalsis.
 There are three sources of digestive secretions that function
within the small intestine: the liver, the pancreas, and the
small intestine itself.
Liver Secretions:
• The cells of the liver have many functions (which are discussed
in a later section), but their only digestive function is the
production of bile.
• Bile enters the small bile ducts, called bile canaliculi, on the
liver cells, which unite to form larger ducts and finally merge to
form the hepatic duct, which takes bile out of the liver.
• The hepatic duct unites with the cystic duct of the gallbladder
to form the common bile duct, which takes bile to the
duodenum.
• Bile is mostly water and has an excretory function in that it
carries bilirubin and excess cholesterol to the intestines for
elimination in feces.
• The digestive function of bile is accomplished by bile salts,
which emulsify fats in the small intestine.
 Bile salt emulsify fatty foods and chemicals.
 Emulsification means that large fat globules are broken into
smaller globules.
 This is mechanical, not chemical, digestion; the fat is still fat but
now has more surface area to facilitate chemical digestion.
 Production of bile is stimulated by the hormone secretin, which is
produced by the duodenum when food enters the small intestine.
 When fatty foods enter the duodenum, the enteroendocrine cells
of the duodenal mucosa secrete the hormone cholecystokinin.
 This hormone stimulates contraction of the smooth muscle in the
wall of the gallbladder, which forces bile into the cystic duct,
then into the common bile duct, and on into the duodenum.
 Detoxification—liver enzymes change potential poisons to less
harmful substances; examples of toxic substances are alcohol,
medications, and ammonia absorbed by the colon.
Pancreas Secretions:
 The exocrine glands of the pancreas are called acini (singular:
acinus).
 They produce enzymes that are involved in the digestion of all
three types of complex food molecules.
 The pancreatic enzyme amylase digests starch to maltose.
 You may recall that this is the “backup” enzyme for salivary
amylase, though pancreatic amylase is responsible for most
digestion of starch.
 Lipase converts emulsified fats to fatty acids and glycerol.
 The emulsifying or fat-separating action of bile salts increases
the surface area of fats so that lipase works effectively.
 Trypsinogen is an inactive enzyme that is changed to active
trypsin in the duodenum.
 Trypsin digests polypeptides to shorter chains of amino acids.
 The pancreas also produces a bicarbonate juice (containing
sodium bicarbonate), which is alkaline.
 Because the gastric juice that enters the duodenum is very
acidic, it must be neutralized to prevent damage to the
duodenal mucosa.
 This neutralizing is accomplished by the sodium bicarbonate in
pancreatic juice, and the pH of the duodenal chyme is raised to
about 7.5.
 Secretion of pancreatic juice is stimulated by the hormones
secretin and cholecystokinin, which are produced by the
duodenal mucosa when chyme enters the small intestine.
 Secretin stimulates the production of bicarbonate juice by the
pancreas, and cholecystokinin stimulates the secretion of the
pancreatic enzymes.
 The secretion of the epithelium of the intestinal glands (or crypts of
Lieberkühn) is stimulated by the presence of food in the
duodenum.
 The intestinal enzymes are the peptidases and sucrase, maltase,
and lactase.
 Peptidases complete the digestion of protein by breaking down
short polypeptide chains to amino acids.
 Sucrase, maltase, and lactase, respectively, digest the
disaccharides sucrose, maltose, and lactose to monosaccharides.
 The enteroendocrine cells of the intestinal glands secrete the
hormones of the small intestine.
 Secretion is stimulated by food entering the duodenum.
ABSORPTION
• Most absorption of the end products of digestion takes place in
the small intestine (although the stomach does absorb water
and alcohol).
• The process of absorption requires a large surface area, which
is provided by several structural modifications of the small
intestine
 The mucosa is folded into projections called villi, which give the
inner surface of the intestine a velvet-like appearance.
 Each columnar cell (except the mucus-secreting goblet cells) of
the villi also has microvilli on its free surface.
 Microvilli are microscopic folds of the cell membrane, and are
collectively called the brush border.
 All of these folds greatly increase the surface area of the
intestinal lining.
Large Intestine:
 The large intestine, also called the colon, is approximately
6.3cm in diameter and 1.5m in length.
 The cecum is the first portion, and at its junction with the ileum
is the ileocecal valve, which is not a sphincter but serves the
same purpose.
 After undigested food (which is now mostly cellulose) and
water pass from the ileum into the cecum,
 The terminal end of the colon is usually referred to as the
rectum.
• Colon parts are: cecum, ascending colon, transverse colon,
descending colon, sigmoid colon, rectum, anal canal.
 No digestion takes place in the colon.
 The only secretion of the colonic mucosa is mucus, which
lubricates the passage of fecal material.
 The functions of the colon are the absorption of water,
minerals, and vitamins and the elimination of undigestible
material.
 About 80% of the water that colon pushes feces into it.
 These waves of peristalsis tend to occur after eating, especially
when food enters the duodenum.
 The wall of the rectum is stretched by the entry of feces, and
this is the stimulus for the defecation reflex.
1.2. Membrane Physiology
• In order for a drug to reach a site of action it must pass from
an ‘external’ site (for example the surface of the skin or the
small intestine) to an ‘internal’ site (the bloodstream or the
cytoplasm of a particular cell group).
• In doing so it will have to pass through a number of tissues
and epithelia, either by going through the cells themselves (and
thus penetrating their plasma membranes) or by finding
pathways between the cells.
• Overcoming these barriers to absorption is one of the most
important considerations in the drug delivery process, and
requires a detailed knowledge of the structure and behaviour of
the cell membranes and epithelial tissues.
• Just as the outer layer of your skin separates your body from
its environment, the cell membrane (also known as the
plasma membrane) separates the inner contents of a cell from
its exterior environment.
 This cell membrane provides a protective barrier around
the cell and regulates which materials can pass in or out.
 Biological membranes consist of lipid bilayer matrices enriched
with integral membrane proteins and membrane-associated
proteins.
 They not only define cells and cell organelles but also represent
the main contact area for intercellular communication, for
which membrane transport and signaling are indispensable.
 This cell membrane provides a protective barrier around the
cell and regulates which materials can pass in or out.
 A single phospholipid molecule has a phosphate group on one
end, called the “head,” and two side-by-side chains of fatty
acids that make up the lipid “tails”
 The lipid tails of one layer face the lipid tails of the other layer,
meeting at the interface of the two layers.
 The phospholipid heads face outward, one layer exposed to the
interior of the cell and one layer exposed to the exterior.
 Unsaturated fatty acids result in kinks in the hydrophobic tails. 
 The phospholipid bilayer consists of two adjacent sheets of
phospholipids, arranged tail to tail.
 The hydrophobic tails associate with one another, forming the
interior of the membrane.
 The polar heads contact the fluid inside and outside of the cell.
 The phosphate group is negatively charged, making the head
polar and hydrophilic
 The lipid tails, on the other hand, are uncharged, or nonpolar,
and are hydrophobic
 Phospholipids are thus amphipathic molecules.
 An amphipathic molecule is one that contains both a
hydrophilic and a hydrophobic region.
 The phosphate groups are attracted to water in the intracellular
fluid. 
 Intracellular fluid (ICF) is the fluid interior of the cell.
 They are also attracted to the extracellular fluid. 
 Extracellular fluid (ECF) is the fluid environment outside the
enclosure of the cell membrane.
 Since the lipid tails are hydrophobic, they meet in the inner
region of the membrane, excluding watery intracellular and
extracellular fluid from this space.
 In addition to phospholipids and cholesterol, the cell
membrane has many proteins also
 The lipid bilayer forms the basis of the cell membrane, but it
is peppered throughout with various proteins.
 Two different types of proteins that are commonly associated
with the cell membrane are the integral protein and
peripheral protein.
 An integral protein is a protein that is embedded in the membrane.
 Many different types of integral proteins exist, each with different
functions.
 For example, an integral protein that extends an opening through the
membrane for ions to enter or exit the cell is known as a channel protein.
 Peripheral proteins are typically found on the inner or outer surface of the
lipid bilayer but can also be attached to the internal or external surface of
an integral protein.
 Some integral proteins serve as cell recognition or surface
identity proteins, which mark a cell’s identity so that it can be
recognized by other cells.
 Some integral proteins act as enzymes, or in cell adhesion,
between neighboring cells.
 A receptor is a type of recognition protein that can selectively
bind a specific molecule outside the cell, and this binding
induces a chemical reaction within the cell.
 Some integral proteins serve dual roles as both a receptor and
an ion channel.
 One example of a receptor-channel interaction is the receptors
on nerve cells that bind neurotransmitters, such as dopamine.
 When a dopamine molecule binds to a dopamine receptor
protein, a channel within the transmembrane protein opens to
allow certain ions to flow into the cell.
 Peripheral proteins are often associated with integral proteins
along the inner cell membrane where they play a role in cell
signaling or attaching to internal cellular components.
 Some integral membrane proteins are glycoproteins.
 A glycoprotein is a protein that has carbohydrate molecules
attached, which extend into the extracellular environment.
 The attached carbohydrate tags on glycoproteins aid in cell
recognition.
 So, the biologic membrane is mainly lipid in nature but contains
small aqueous channels or pores
 Tight junctions are formed when specific proteins in two adjacent
plasma membranes make direct contact across the intercellular
space
 The blood brain barrier (in the CNS) and placental is a tight
junctions between the cells
 These features prevent potentially harmful molecules from leaking
from the blood into these organs and have major pharmacokinetic
consequences for drug distribution
 CHAPTER-2
MAIN FACTORS AFFECTING ORAL ABSORPTION
2.1. Physiological factors affecting oral absorption
 The oral absorption process of drug from a pharmaceutical
dosage form is very complex.
 The major steps occurring during oral drug absorption can be
regarded as part of a serial process:
(1) The dissolution of the drug from the dosage form ；
(2) The solubility of drug as a function of its physicochemical
characteristics ；
(3) The drug’s effective permeability to the intestinal mucosa ；
(4) The drug’s pre-systemic metabolism.
 Physiological factors are:
 Oral Drug absorption can be affected by GIT pH, gastric
motility, Gastric empyting time, small intestinal transit time,
bile salt, slanchic blood flow, enterohepatic circulation, disease
state, absoption mechanism, and plasma membrane nature.
1. Gastric motility-gastrointestinal motility refers to the
movement of ingested things from the mouth through the
pharynx (throat), esophagus, stomach, small and large
intestines and out of the body. 
 Gastric motility is important for the proper processing and
gastric emptying of an ingested meal and drugs.
 The gastric motility responses to an ingested meal involve
actions of several different regions of the stomach.
 These include initial proximal gastric fundic relaxation and
accommodation of the meal followed by subsequent tonic
fundic contractions.
 It has large effect.
 Some disorders like diabetic neuropathy causes gastric stasis
and decrease the drug absorption.
 Due to drug treatment, some time motility is increased or
decreased.
 Symptoms and clinical disorders referable to the upper
digestive tract may be associated with various abnormalities
in gastric motility and function including: the rate of gastric
emptying, impaired accommodation, alterations in gastric
myoelectrical motor function, impaired antral contractility,
heightened gastric sensation, pyloric sphincter dysfunction,
and abnormal duodenal contractility affect motility rate.
 The excessively rapid movement of GIT impairs absorption.
 Because, by movement of GIT wall, the drug particle can
easily comes in contact with mucosa and get absorbed, so
due to faster movement of GIT, the drug particles are not
able to come in contact with mucosa.
• The rate of gastric emptying affects all drugs, even those
which are well absorbed in the stomach.
• Gastric motility is a major determinant of oral drug
absorption.
• Few drugs are absorbed in the stomach for two main
reasons. 
 Firstly, the stomach lining is coated with a thick protective
mucus which makes diffusion difficult.
 Secondly, the stomach has a fairly small surface area
when compared to the small bowel.
• The consequences of this are that the stomach participates
minimally in drug absorption, and any situation which
involves drugs sitting in the stomach for a long time will
result in poor drug bioavailability.
• Thus, gastric emptying rate is one of the main determinants
of oral drug bioavailability and gastrointestinal drug
absorption.
• If the stomach does not empty, practically nothing is going to
get absorbed.
• Even drugs which are undissociated in gastric acid and fully
dissociated in the small bowel are still predominantly
absorbed in the small bowel because of its comparatively
massive surface area.
• In brief summary, gastric emptying can be affected by:
 Food in the stomach (especially fat)
 Viscosity of the stomach content
 Size of the tablet or capsule 
 Drugs
 Autonomic and hormonal activity
•  
2. Ionization and gastric emptying
Acidic drugs are absorbed faster in acidic pH because acidic
drugs remain unionized in acidic medium (stomach).
 So they can be absorbed through lipidic cell membrane.
 Basic drugs are not absorbed well in acidic pH because the
basic drugs ionize in acidic medium.
 Basic drugs remain unionize in basic medium (small intestine)
and can be easily absorbed.
 Acidic drugs ionize in basic medium so can’t be absorbed.
 Thus, if acidic drugs remain for long time into stomach, they
get absorbed at a faster rate.
 And if basic drug remains for a short time in stomach and
being more time in small intestine, they get easily absorbed.
 It means, for acidic drug gastric emptying time should be more
and for basic drugs gastric emptying time should be faster.
3. Splanchnic blood flow
 Some drugs are achieving higher plasma conc. after food, this
is because food increase splanchnic blood flow.
 Example: propranolol, chloramphenicol, lithium carbonate.
 The absorption of some drugs is reduced due to presence of
food like ampicillin, aspirin, L-dopa.
 In hypovalemic state, the splanchnic blood flow is reduced. So
absorption of the drug is also decreased.

   4. Enterohepatic circulation

 This increases bioavailability of the drug.
 For example, morphine.The morphine is less potent when
given orally. It undergoes enterohepatic cycling.
 If there is more cycling of drugs, then more absorption of
drugs will occur.
5. Metabolism of drug in GIT wall
 If any drug is undergoing first pass metabolism and it may be
degraded by liver or by the enzyme present in the gut, the
bioavailability of the drug is decreased.
 Thus drug absorb well after oral administration but may not be
effective due to first pass metabolism.
6. Pharmacogenetic factors-A study of variability of action of
drug in different human is called as pharmacogenetic.
 Enzymes influencing metabolic rxns are under genetic control.
 Differences observed in the metabolism of the drug among
different races are called ethnic variation.
 For example, alcohol dehydrogenase enzyme, present in gastric
mucosa, converts the alcohol into acetaldehyde, which is not
intoxicating.
 Females and Asian males have less quantity of this enzyme.
 So they often develops more adverse effect of alcohol than
other men.
7. Disease state
• Gastrointestinal disease may also alter oral dose requirements
by producing variation in both the amount and rate of drug
absorption.
• These changes may be reflected in the plasma
concentration/time curve that follows an oral dose.
• Some diseases like malabsorption, thyrotoxicosis, achlohydria,
cirrhosis of liver and billiary obstruction can affect he
absorption & bioavailability of drugs.
• In case of malabsorption the pseudotolerance is developed and
drug can’t be absorbed.
• In thyrotoxicosis(hyperthyroidism), the weight loss occurs due
to less appetite.
• In achlorhydria(decrease in HCL level in stomach), acidic drug
can’t be absorbed.
• In cirrhosis of liver the drug is more metabolized and produces
toxic effect.
Intestinal Transit Time
• The intestinal drug absorption is important for the oral drug
delivery system and its potential is associated with enzymatic and
physical environment of the GIT.
• After drug administration, the drug reaches the harsh environment
of the stomach or entire length of GIT secreted the digestive
enzymes, where it can be degraded so stability is compromised.
• This can be overcome with the help of various polymeric systems
to enhance the intestinal absorption of hydrophilic or hydrophobic
drugs.
• They have the potential to pass through the stomach and
ultimately, after reaching the intestine, release the drugs.
• Various polymers, such as polysaccharides (chitosan or dextran),
acrylic copolymers (Eudragit), phospholipids, or cellulosic
derivatives, represented the adequate gastroresistant properties
and easily pass intact through the stomach, reaching the
intestines and releasing the drug. 
8. Route of administration
• Parenterals are absorbed at a faster rate than oral
administration.
• Bioavailability of  intra venous is 100%.
• Some drugs like insulin can’t be given by oral route due to
destruction by GIT enzymes.
• Thus, the drug is to be administered by the selective route.
9. Presence of other substance
• Vitamin C favours the absorption of iron from GIT while tannin
which is found in tea retard its absorption.
• Absorption of fat soluble vitamin is increased in presence of
liquid paraffin.
• Cholesterol absorption is reduced by sitosterol and calcium
complexes with tetracyclines & retards its release from drug
and decrease absorption.
• Some drugs have a short transit time, leading to incomplete
absorption with poor bioavailability.
• The researchers paid attention to the fact that by using
mucoadhesive dosage forms, the duration of time can be improved.
• The mucoadhesive systems have potential benefits, such as
increased local drug concentrations, which is favorable to absorption,
improving the drug effectiveness by maintaining their plasma drug
concentration, and in some cases specially restricting absorption to a
particular site in the intestine. 
• When a drug is taken orally, it must be able to survive the low pH
and presence of potentially degrading enzymes in the gastrointestinal
tract before it can be absorbed into the bloodstream.
• Some peptide drugs such as insulin cannot be given orally for this
reason.
• There are some drug formulations that manipulate the properties of
the drug to control the process of absorption.
• These are referred to as controlled-release medications.
Intestinal blood flow:
• Blood flow assures continuous absorption by removing drug
that passes through the membranes of the gastrointestinal
wall.
• If a highly lipid-soluble drug passes very rapidly across the
gut wall, the rate-limiting step in the absorption of that drug
may be the rate of intestinal blood flow, and its ability to
carry away absorbed drug.
• In practice, very few drugs are absorbed rapidly enough for
blood flow to be a rate limiting factor, but ethanol and
methanol are examples of such drugs.
2.1.2. Drug Transport in Cell Membrane
 There are four possible mechanisms for the absorption of a drug from
solution in the gastrointestinal fluids.
1. Passive diffusion:
 This is the most usual mechanism for the absorption of drugs across
a membrane such as the lining of the gastrointestinal tract.
 Passive diffusion is the natural tendency for molecules to move from a
region of high concentration to one of low concentration, such as in
 the blood.
 In order to be absorbed, a drug molecule must be in solution at the
surface of the cell membrane, and its lipid solubility must enable it to
dissolve in the hydrophobic inner layers of the cell membrane.
 Finally the molecule passes out into the aqueous phase inside the cell.
 Drug absorption depends, in this situation, largely on the
physicochemical properties of the drug, although the surface area of
the gut available for absorption is of considerable importance.
 The rate of penetration by a drug through the cell membrane is
expressed in terms of the permeability constant:
 Thus, increased thickness of the membrane is accompanied by
a reduction in the rate of absorption.
 The major source of variation in absorption is the partition
coefficient of a drug between lipid membrane and aqueous
surroundings.
 Lipid soluble drugs have high permeability constants and
penetrate cell membranes with ease.
 Water soluble (or hydrophilic) drugs partition poorly into lipids
and thus pass through the membrane rather slowly.
 Thus, for absorption, a drug must possess a balance of water
solubility, so that it can dissolve in the aqueous phase at the
cell surface, and lipid solubility so that it can penetrate the
membrane.
 This is a passive process that does not require energy, and the
rate of diffusion is directly proportional to the concentration
gradient.
 Other factors influencing passive diffusion include:
 the physicochemical properties of the drug, such as its:
 Lipid solubility
 Molecular size
 Degree of ionization
 the absorptive surface area available to the drug.
 In general, lipid-soluble drugs, and drugs composed of
smaller molecules, cross the cell membrane more easily and
are more likely to be absorbed by passive diffusion.
 As most drugs are weak acids or bases, they exist in the
form of an equilibrium between the ionized and un-ionized
form in an aqueous environment, such as the gastrointestinal
tract.
 The un-ionized form usually diffuses across the cell
membrane more readily as it is more lipophilic.
 The ionized form, on the other hand, exhibits high electrical
resistance and is less likely to diffuse across the membrane.
 The ratio of the un-ionized form depends on the environmental
pH and the acid dissociation constant (pKa).
Factors that Govern Passive Diffusion:
1.The lipid solubility of a chemical: This is a characteristic
expressed in terms of the ability of a chemical to partition
between oil and water phases. The more a chemical dissolves
in oil, or its substitute octanol, the more lipid soluble it is and
more easily crosses membranes.
2.The degree of ionization (electrical charge) of a chemical: As a
rule, electrically neutral chemicals permeate more easily
through the lipid phase of a membrane due to their higher
degree of lipid solubility.
3.The molecular size of a chemical: Passive diffusion is normally
limited to chemicals with molecular weight ≤500 Da. A small
molecule will cross membranes more rapidly than a larger one
Facilitated Passive Diffusion:
 This refers to the passage of certain drugs across cell membranes
according to the concentration gradient, but in association with
specific substrate molecules which attach the drug molecule and
diffuse across the membrane.
 This does not require energy.
 Certain molecules with low lipid solubility (eg, glucose) penetrate
membranes more rapidly than expected by facilitated diffusion
  A carrier molecule in the membrane combines reversibly with the
substrate molecule outside the cell membrane, and the carrier-
substrate complex diffuses rapidly across the membrane, releasing
the substrate at the interior surface.
 In such cases, the membrane transports only substrates with a
relatively specific molecular configuration, and the availability of
carriers limits the process.
 The process does not require energy expenditure, and transport
against a concentration gradient cannot occur.
2. Active transport
 This term implies the utilization of energy to convey a drug
across a cell membrane, usually against a concentration
gradient.
 This mechanism is normally highly specific for the substrate
carried, for example amino-acids, and is not really of
importance for the absorption of drugs.
 Active transport is involved in the renal excretion of many acids
(e.g. penicillin) and bases, but the only drugs of which the
absorption may be mediated by active transport are
methyldopa, levodopa and 5-fluorouracil.
 Active transport requires energy to facilitate the transport of
drug molecules against a concentration gradient, which usually
occurs at specific sites in the small intestine.
 The majority of drugs that are absorbed via active transport
share a similar structure with endogenous substances such as
ions, vitamins, sugars and amino acids.
3. Filtration through pores
 There are known to be pores between cells which may allow
the passage of drugs and other molecules.
 These pores are very small, and the total area of the pores is
small compared with the total cell membrane area.
 Cpds require a molecular weight of less than 100 to traverse
these pores and most drugs have molecular weights between
100 and 350.
 Thus, only compounds such as ethanol and methanol (which
are water soluble) are likely to use this route of absorption, and
there is considerable doubt over its role in the absorption of
drugs.
4. Pinocytosis:
 The mechanism of absorption, whereby microscopic particles
are engulfed by the cell membrane
 It may be relevant to the uptake of macromolecules.
 Pinocytosis involves absorption of fluid or particles following
their encapsulation by a cell.
 The membrane of the cells closes in around the
pharmacological substance and fuses to form a complete
vesicle, which later detaches and moves into the inside of the
cell.
 This process also requires energy to occur.
Ion pair formation
 When special structural and solvation requirements are met, oppositely
charged compounds can form a new species, the ion pair.
 The ion pairs of interest are electrically neutral and usually have a
measurable lipid solubility; they can often be moderately to very soluble in
such weakly polar solvents as chloroform and n-octanol.
 Because the ion pair is in equilibrium with the two component ions, an
excess of one ion results in a larger fraction of the second ion being in the
ion pair state.
 The normally lipid-soluble paired ion may be regarded as a prodrug.
 It may diffuse through the lipoidal regions of the intestinal membranes to
reach the blood.
 Oral Administration
• To be absorbed, a drug given orally must survive encounters
with low pH and numerous gastrointestinal (GI) secretions,
including potentially degrading enzymes.
• Peptide drugs (eg, insulin) are particularly susceptible to
degradation and are not given orally.
• Absorption of oral drugs involves transport across membranes
of the epithelial cells in the GI tract. Absorption is affected by
– Differences in luminal pH along the GI tract
– Surface area per luminal volume
– Blood perfusion
– Presence of bile and mucus
– The nature of epithelial membranes
• The oral mucosa has a thin epithelium and rich vascularity,
which favor absorption; however, contact is usually too brief
for substantial absorption.
 A drug placed between the gums and cheek (buccal
administration) or under the tongue (sublingual
administration) is retained longer, enhancing absorption.
 Lipid-soluble drugs are absorbed more rapidly than non–lipid-
soluble drugs.
 Gastric fluid has a pH of approximately 1.4.
 Drugs that are organic acids, such as aspirin, freely diffuse
across the gastric mucosa into the circulatory system.
 Drugs that are bases (e.g., codeine) are poorly absorbed
from the highly acid environment of the stomach.
 As gastric fluid leaves the stomach to enter the small
intestine, its pH changes dramatically as a result of the
addition of biliary, intestinal, and pancreatic secretions.
 In the intestinal environment, with its pH of approximately
4.0 to 6.0, the absorption of aspirin is slowed, whereas
absorption of the more basic codeine is accelerated.
 With increased age, many physiological changes occur, which
may lead to decreased drug absorption.
 Critically ill patients may have reduced blood flow to the GI
tract, which will result in reduced drug absorption.
 Generally, intestinal absorption is more critical for most drugs
than any other site in the GI tract due to the increased
surface area of the intestinal mucosa.
 The duodenal mucosa has the quickest drug absorption
because of such anatomical characteristics as villi and
microvilli, which provide a large surface area.
 However, these villi are much less abundant in other parts of
the GI tract.
 Characteristics of the gut content (eg. Food or drug
interaction)
1. Effect of food on drug absorption
 Food content appears to affect the absorption rate of many
orally administered drugs.
 Drug-food interactions take place mechanistically due to altered
intestinal transport and metabolism, or systemic distribution,
metabolism and excretion
 For example, the absorption rate of levodopa, an
antiparkinsonian drug, is decreased when administered with
protein-containing food.
 While the absorption of albendazole, an antiprotozoal agent, is
enhanced with lipid-containing food.
 Based on the physicochemical properties of the compounds,
physiological changes induced by the intake of food mainly
happen in slowing of gastric emptying rate and the increase in
gastric pH.
 The pH differences in the contents of the upper GI tract
between fed and fasted states can influence the dissolution and
absorption of weakly acidic and basic drugs.
 Elevation of gastric pH following a meal may enhance the
dissolution of a weak acid in the stomach but inhibit that of a
weak base.
 Dairy products such as milk, yogurt, and cheese can interfere
with certain medications, including antibiotics such as
tetracycline, doxycycline, and ciprofloxacin.
 These antibiotics may bind to the calcium in milk, forming an
insoluble substance in the stomach and upper small intestine
that the body is unable to absorb.
 Patients should avoid eating grapefruit or drinking grapefruit
juice while taking some medications, in particular statins.
 Taking alcohol with metronidazole can cause flushing,
headache, palpitations, nausea and vomiting.
 2.2. Physical-Chemical Factors Affecting Oral Absorption
1) Drug solubility & dissolution rate
2) Particle size & effective surface area
3) Polymorphism & amorphism
4) Pseudopolymorphism (hydrates/solvates)
5) Salt form of the drug
6) Lipophilicity of the drug (pH- Partition-hypothesis)
7) pKa of drug & gastrointestinal pH
8) Drug stability
1) Drug solubility & dissolution rate:
 Absorption of a drug is possible only when it is present in the
solution form, wherein the molecules are independent &
assume molecular dimensions.
 Dissolution is the process where a solute in gaseous, liquid, or
solid phase dissolves in a solvent to form a solution. 
 Solubility is the maximum concentration of a solute that
can dissolve in a solvent at a given temperature.
 At the maximum concentration of solute, the solution is said to
be saturated.
 Solubility is one of the important parameters to achieve
desired concentration of drug in systemic circulation for
achieving required pharmacological response.
 Poorly water soluble drugs often require high doses in order to
reach therapeutic plasma concentrations after oral
administration
 The poor solubility and low dissolution rate of poorly water
soluble drugs in the aqueous gastrointestinal fluids often cause
insufficient bioavailability.
Dissolution, or in vitro release, of the drug substance from the product
into a typically aqueous-based medium, is linked to the release of the
drug into the body, making it available for absorption, and then efficacy
or clinical outcome.
 Dissolution testing is primarily used in industry as a quality control tool
to monitor the formulation and manufacturing processes of the dosage
form.
 The regulatory agencies use the dissolution test to provide a quality
connection from a pivotal biobatch to the commercialized product.
 For this reason, the dissolution test development and validation are
critical factors in insuring that the test is robust and clinically relevant.
  The rate of drug dissolution of a drug will exert a direct impact on
bioavailability and drug delivery aspects.
 Dissolution can be defined as the process through which drug particles
tend to dissolve in the body fluids.
 Any change in drug dissolution will significantly affect the bioavailability.
 The modified Noyes–Whitney equation describes the drug dissolution in
which surface area is constant during disintegration.
where, D=diffusion coefficient of the drug in the dissolution medium.
• h=thickness of the diffusion layer at the solid/liquid interface.
• A=surface area of drug exposed to dissolution medium.
• V=volume of the medium.
• CS=Concentration of saturated solution of the solute in the dissolution
medium at the experimental temperature.
• C=Concentration of drug in solution at time t.
• When A=constant and CS≫C the equation can be rearranged to
• The rate determining steps in absorption of orally administered
drugs are:
1. Rate of dissolution
2. 2. Rate of drug permeation through the bio-membrane.
• Dissolution is the rate determining step for hydrophobic &
poorly aqueous soluble drugs. E.g. Griesiofulvin &
Spironolactone.
• Permeation is the rate determining step for hydrophilic & high
aqueous soluble drugs. E.g. Cromolyn sodium OR Neomycin.
• Absolute Solubility or intrinsic solubility is defined as ………….. “
The maximum amount of solute dissolved in the given solvent
under standard conditions of temperature, pressure & pH.
• In order to avoid bioavailability problems, the drug must have a
minimum aqueous solubility of 1%.
2) Particle size & effective surface area
 Particle size plays a major role in drug absorption & this case is
important when the drug is poorly soluble (aqueous solubility).
 Smaller particle size, greater surface area then higher will be
dissolution rate, because dissolution is thought to take place at
the surface area of the solute( Drug).
 Particle size reduction has been used to increase the absorption
of a large number of poorly soluble drugs E.g. Bis-
hydroxycoumarin, digoxin, griseofulvin
 Types of surface area: 1) Absolute surface area 2) Effective
surface area
 Absolute surface area is the total area of the solid surface of
any particle and an effective surface area is the area of the
solid surface exposed to the dissolution medium.
 In absorption studies, the effective surface area is of much
important than absolute.
 To increase the effective surface area, we have to reduce the
size of particles up to 0.1 micron.
 So these can be achieved by “micronisation process’’.
 When a drug is said to be micronized, that means its particle
size is generally less than 50 microns.
 When an API is micronized, its particle size is about 4 to 10
times smaller than conventional drug particles.
 Micronization technology has improved drug bioavailability in
medicine ever since its discovery.
 But in these cases, one of the most important thing to be kept
in mind that what type of drug is need to be micronised if it is:
a) Hydrophilic: In hydrophilic drugs, the small particles have
higher energy than the bulk of the solid resulting in an
increased interaction with the solvent.
• Examples:
• 1.Griesiofulvin – Dose reduced to half due to micronisation.
2.Spironolactone – the dose was decreased to 20 times.
3.Digoxin – the bioavailability was found to be 100% in
micronized tablets.
• After micronisation, it was found that the absorption efficiency
was highly increased
b) Hydrophobic Drugs: In this, micronization techniques results in
decreased effective surface area & thus fall in dissolution rate.
 Reasons for such change involves:  Air entrapment –
wettability  Surface free energy – float or sink  Such
problems can be prevented by: a) Use of surfactant as a
wetting agent which - decreases the interfacial tension. -
displaces the absorbed air with the solvent. (Ex: Phenacetin) b)
Add hydrophilic diluents like PEG, PVP, dextrose etc. (which
3) Polymorphism & amorphism
 Polymorphs are the types of morphological structures which
differ in molecular packing (crystal structure), but share the
same chemical composition.
 The word “Polymorphs” refers to the existence of the same
material in more than one morphological forms like crystals,
amorphous, etc.
 Polymorps are of two types:
a) Enantiotropic polymorph (E.g. Sulfur)
b) Monotropic polymorph (E.g. Glyceryl stearates)
- Polymorphism has profound influence on formulation
development as it may exhibit different solubility, dissolution
rate, compactibility, hygroscopicity,etc.
- E.g. Chloramphenicol palmitate exists in three crystalline forms
A, B and C. A-is the stable polymorph; B- is the metastable
polymorph (more soluble); C- is the unstable polymorph
-
• The plasma profiles of chloramphenicol from oral
suspensions containing different proportions of Polymorphic
forms A and B were investigated
• The extent of absorption of Chloramphnicol increases as the
proportion of the polymorphic form B is increased in each
suspension
• This is attributed to the more rapid Dissolution of the
metastable Polymorphic form B

- Shelf-life could be a problem as the more soluble (less stable)

form may transform into the less soluble form (more stable)
 Amorphism: Some drugs can exist in amorphous form (i.e. having no ordered
internal crystal structure).
 The amorphous form dissolves more rapidly than the corresponding crystalline form
 The more soluble and rapidly dissolving amorphous form of novobiocin antibiotic
was readily absorbed following oral administration of an aqueous suspension to
humans.
 The amorphous form of Novobiocin is 10 times more soluble than the crystalline
form.
 However, the less soluble and slower-dissolving crystalline form of novobiocin was
not absorbed (therapeutically ineffective)
 The amorphous form of novobiocin slowly converts to the more stable crystalline
form, with loss of therapeutic effectiveness
 Such drug represents the highest energy state. They have greater aqueous
solubility than the crystalline forms because a energy required to transfer a
molecule from the crystal lattice is greater than that required for non-crystalline
(amorphous form).
 Thus, the order of different solid dosage forms of the drugs is: Amorphous > Meta-
stable > stable
4) Pseudopolymorphism (hydrates/solvates)
 Pseudopolymorphs: When the solvent molecules are entrapped
in the crystalline structure of the polymorph, it is known as
pseudo-polymorphism.
 Types: Solvates “the stoichiometric type of adducts where the
solvent molecules are incorporated in the crystal lattice of the
solid are called as the solvates, and the trapped solvent as
solvent of crystallization.”
 Hydrates “when the solvent in association with the drug is
water , the solvate is known as a hydrate.”
 Ex: n-pentanol solvates of flurocortisone and succinyl-
sulfathiazole
5) SALT FORMS
 Salt forms of drug is a method of converting a drug into its salt form by virtue
of which its solubility, dissolution & thereby absorption increases to many
folds comparatively.
 While considering the salt form of drug, pH of the diffusion layer is important
not the pH of the bulk of the solution.
 Example: Salt of weak acid - It increases the pH of the diffusion layer, which
promotes the solubility and dissolution of a weak acid and absorption is
bound to be rapid.
 Bulk of solution relatively lower pH(1-3) Diffusion of soluble drug particles GI
Lumen Soluble form of the drug rapid dissolutio n GI Barrier drug in solution
diffusion layer higher pH(5- 6) Blood Drug in blood fine precipitate of weak
acid
 Other approach: Formation of in – situ salt formation i.e…… “increasing in pH
of microenvironment of drug by incorporation of a buffering agent.” (E.g.
aspirin, penicillin)
 But sometimes more soluble salt form of drug may result in poor absorption.
(Ex: Sodium salt of phenobarbitone viz., its tablet swells and did not get
disintegrate, thus dissolved slowly and results in poor absorption)
6) pH Partition Hypothesis:
• The theory expresses the interrelationship of Dissociation
Constant & Partition Co-efficient of the drugs with the pH of
GIT for predicting the drug absorption.
• It states that…… “for drug compounds of molecular weight
more than 100, which are primarily transported across the bio-
membrane by passive diffusion” the process of absorption is
governed by:
• 1. The dissociation constant pKa of the drug.
• 2. The lipid solubility of the un-ionized drug.
• 3. The pH at the absorption site.
• Brodie et al. (Shore, et al. 1957) proposed the pH - partition
theory to explain the influence of GI pH and drug pKa on the
extent of drug transfer or drug absorption.
• Brodie reasoned that when a drug is ionized it will not be able
to get through the lipid membrane, but only when it is non
ionized and therefore has a higher lipid solubility.
A) Drug pKa and GI pH: Amount of drug that exists in un-ionized form and in
ionized form is a function of pKa of drug and pH of the fluid at the
absorption site
 The degree of ionization (pKa) of a drug is a unique physicochemical
property that controls its ionization state when in solution.
 If the drug's pKa is the same as the pH of the solution it is dissolved in,
then 50% of the drug exists in ionized form, and 50% exists in unionized
form.
 pKa is the pH at which the ionized and unionized forms exist in equal
concentrations.
 As the pH of the solution changes, the state of ionization changes as well.
 Ionized compounds are less lipophilic and are less able to pass through
a lipid bilayer.
 The newly ionized form of the drug may have difficulty diffusing back 
 The absorption of a drug depends on its lipid solubility and inversely on its
polarity or degree of ionization.
 An important factor in the degree of penetration of a drug through
membranes is that many drugs are weak acids or weak bases.
 The more the drug is in its un-ionized form, the more likely it is
to be lipid-soluble and transferred by passive diffusion through
the membrane. 
 For a weak acid or base, the pKa value will determine the degree
of ionization, as described by the Henderson–Hasselbalch
equation.
 For a weak acid the ionizing reaction is:

 At physiologic pH, the lower the pKa the greater the lipophilicity. 
 The relative concentration of drug in each compartment can be calculated
with the Henderson-Hasselbalch equation, as follows:

 Because few organic acids have a pKa low enough to permit significant

ionization at stomach pH, almost all acidic drugs should theoretically be
effectively absorbed across the gastric mucosa.
 For bases such as codeine (pKa 7.9), the opposite applies.
 Codeine is almost completely ionized in the acidic environment of the
stomach; absorption is negligible, it needs to be absorbed in intestine.
• A substance will become more lipid soluble in a solution with a pH
similar to its own pH.
A weak acid is more lipid-soluble in an acidic solution
A weak base is more lipid-soluble in an alkaline solution.
A weak acid is more WATER-soluble in an alkaline solution
A weak base is more WATER-soluble in an acidic solution.
Limitations of the pH-partition hypothesis:
Despite their high degree of ionization, weak acids are highly
absorbed from the small intestine and this may be due to:
a. The large surface area that is available for absorption in the
small intestine
b. A longer small intestine residence time
c. A microclimate pH, that exists on the surface of intestinal
mucosa and is lower than that of the luminal pH of the small
intestine
7. Lipid solubility of drugs
- Non-ionized form of some drugs are poorly absorbed from
small intestine- Low lipid solubility of them may be the reason
- The best parameter to correlate between water and lipid
solubility is partition coefficient.
Partition coefficient (p) = [ L] conc / [W] conc
- The higher p value, the more absorption is observed
8) Drug stability and GIT secretions effect
 Drug stability means the ability of the pharmaceutical dosage form to
maintain the physical, chemical, therapeutic and microbial properties during
the time of storage and usage by the patient.
 It is measured by the rate of changes that take place in
the pharmaceutical dosage forms.
 Drug for oral use may be destabilized either during its shelf life/in the GIT.
 Two major stability problems resulting in poor bioavailability of an orally
administered drug are:
 Degradation of the drug into inactive form ex: Penicillin G (enzymatic
degradation) ex: Ampicillin (in place of penicillin due to resistance)
 Interaction with one or more different component(s) either of the
dosage form or those present in the GIT to form a complex that is poorly
soluble or is unabsorbable.
 The stability profile of drugs in GI conditions must be studied before
selecting a particular drug for improved dissolution.
 Drug stability affects the safety and efficacy of the drug product;
degradation impurities may cause a loss of efficacy and generate possible
adverse effects. Therefore, achieving the chemical and
physical stability of drugs is essential to ensure their quality and safety.
 Disintegration of dosage form and dissolution of drug can be
controlled by formulation but can be affected by peristaltic
movement, luminal pH, and the release of bile salts and the
presence of food.
 For most of the drugs (excluding some sustained release
formulations) absorption occurs from duodenum and jejunum.
 GI enzymes, which contribute for presystemic metabolism of a
drug, are categorized as:
(1) Luminal enzymes
(2) Gut wall/mucosal enzymes
(3) Bacterial enzymes.
9. Drug Complexation
 Complexation is used to characterize the covalent or
noncovalent interactions between two or more compounds that
are capable of independent existence.
 Drug molecules can form complexes with other small molecules
or with macromolecules such as proteins.
 There are numerous types of complexes and some are more
water-soluble than others.
 Coordination complexes consist of drugs that act as complexing
agents (i.e. ligands) and metal ions (i.e. substrates).
 Examples of coordination complexes are some water-soluble
tetracycline-metal ion complexes.
 The ligand is a molecule that interacts with another molecule,
the Drug, to form a complex.
 Drug molecules can form complexes with other small molecules
or with macromolecules such as proteins.
 Once complexation occurs, the physical and chemical properties
of the complexing species altered are; Solubility, Stability,
Partition co-efficient, and Energy absorption.
 In some instances, complexation also can lead to poor solubility
or decreased absorption of drugs in the body.
 For some drugs, complexation with certain hydrophilic
compounds can enhance excretion.
 Complexation process reduces the absorption of Tetracycline by
complexing with cations like Ca+2, Mg+2 and Al+3 .
 Complexation process enhances the aborption of
Indomethacine and Barbiturates by complexing with β-
cyclodextrine.
 Tetracycline and Calcium – Poor absorbed complex.
 Polar drug and complexing agent – Well absorbed lipid soluble
complex.
 Carboxy methyl cellulose and amphetamine – Poor absorbed
complex.
 PVP and I2 – Better absorption.
 The Comlexation of drug with polymers used in the formulation
of sustained drug delivery device.
10. Drug Adsorption in GIT
• Certain insoluble susbstances may adsorbed co-administrated
drugs leading to poor absorption
– Charcoal (antidote in drug intoxication)

– Kaolin (antidiarrhoeal mixtures)

– Talc (in tablets as glidant)
2.3. Formulation Factors Affecting Oral Absorption (2hrs)
Solutions, Suspensions, Capsules, Tablets

Formulation factors affecting drugs absorption characteristics,

include:
 Disintegration time (tablets/capsules)

 Dissolution time
 Manufacturing variables
 Pharmaceutical ingredients (excipients/adjuvants)

 Nature & type of dosage form

 Product age & storage condition
2) Dissolution time
 Many drugs are given in solid dosage forms must dissolve
before absorption can take place

 If dissolution is the slow, it will be the rate determining step

(the step controlling the overall rate of absorption) then factors
affecting dissolution will control the overall process
 The rate of absorption of poorly soluble drugs is dissolution
rate-limited.
 Slow dissolution results in incomplete, erratic and unpredictable
absorption.
• Since a drug must be in solution to be absorbed efficiently from the G-I
tract, you may expect the bioavailability of a drug to decrease in the
order: solution > suspension > capsule > tablet > coated tablet

A. Solution dosage forms:

• In most cases absorption from an oral solution is rapid and complete,
compared with administration in any other oral dosage form
• Some drugs which are poorly soluble in water may be:

1. Dissolved in mixed water/alcohol or glycerol solvents (cosolvency),

2. Given in the form of a salt (in case of acidic drugs)

3. An oily emulsion or soft gelatin capsules have been used for some
compounds with lower aqueous solubility to produce improved
bioavailability
B. Suspension dosage forms
- A well formulated suspension is second to a solution in terms of
superior bioavailability
- A suspension of a finely divided powder will maximize the
potential for rapid dissolution
- A good correlation can be seen for particle size and absorption
rate
- The addition of a surface active agent will improve the
absorption of very fine particle size suspensions
C. Capsule dosage forms
- The hard gelatin shell
- should disrupt rapidly and allow the contents to be mixed with the
GIT contents
- If a drug is hydrophobic a dispersing agent should be added to the
capsule formulation
- These diluents will work to disperse the powder, minimize
aggregation and maximize the surface area of the powder
- Tightly packed capsules may have reduced dissolution and bioavailability
D. Tablet dosage forms:
- The tablet is the most commonly used oral dosage form

- It is also quite complex in nature

- Rate of disintegration of tablet

– Tablet compression
– Bulk excipients
 CHAPTER-3

PRINCIPLES OF THE BIOAVAILABILITY

OF DRUGS
 Background: What is Bioavailability?
 Bioavailability is the rate and extent to which the active
ingredient is absorbed from a drug product and becomes
available at the site of action.
 For drug products that are not intended to be absorbed into
the bloodstream, bioavailability is the rate and extent to
which the active ingredient becomes available at the site of
action.
 Since pharmacologic response is generally related to the conc
of drug at the receptor site, the availability of a drug from a
dosage form is a critical element of a drug product’s clinical
efficacy.
 However, drug conc s usually cannot be readily measured
directly at the site of action.
 Therefore, most bioavailability studies involve the
determination of drug conc in the blood or urine.
 This is based on the premise that the drug at the site of
action is in equilibrium with drug in the blood.
 It is therefore possible to obtain an indirect measure of drug
response by monitoring drug levels in the blood or urine.
 Thus, bioavailability is concerned with how quickly and how
much of a drug appears in the blood after a specific dose is
administered.
 The bioavailability of a drug product often determines the
therapeutic efficacy of that product since it affects the onset,
intensity and duration of therapeutic response of the drug.
 In most cases one is concerned with the extent of absorption of
drug, (that is, the fraction of the dose that actually reaches the
bloodstream) since this represents the "effective dose" of a
drug.
 This is generally less than the amount of drug actually
administered in the dosage form.
 In some cases, notably those where acute conditions are
being treated, one is also concerned with the rate of
absorption of a drug, since rapid onset of pharmacologic
action is desired.
 Conversely, these are instances where a slower rate of
absorption is desired, either to avoid adverse effects or to
produce a prolonged duration of action.
• "Absolute" bioavailability, F, is the fraction of an administered
dose which actually reaches the systemic circulation, and
ranges from F = 0 (no drug absorption) to F = 1 (complete
drug absorption).
 Since the total amount of drug reaching the systemic circulation
is directly proportional to the area under the plasma drug conc
as a function of time curve (AUC), F is determined by comparing
the respective AUCs of the test product and the same dose of
drug administered intravenously.
 The intravenous route is the reference standard since the dose
is, by definition, completely available. , (where
AUCEV and AUCIV are, respectively, the area under the plasma
conc- time curve following the extravascular and intravenous
administration of a given dose of drug.
 Knowledge of F is needed to determine an appropriate oral dose
of a drug relative to an IV dose.
 "Relative" or “Comparative” bioavailability refers to the
availability of a drug product as compared to another dosage
form or product of the same drug given in the same dose.
 These measurements determine the effects of formulation
differences on drug absorption.
 The relative bioavailability of product A compared to product B,
both products containing the same dose of the same drug, is
obtained by comparing their respective AUCs.

,where drug product B is the reference standard.

 When the bioavailability of a generic product is considered, it is
usually the relative bioavailability that is referred to.
 A more general form of the equation results from considering the
possibility of different doses,

 The difference between absolute and relative bioavailability is

illustrated by the following hypothetical example.
 Assume that an intravenous injection (Product A) and two oral
dosage forms (Product B and Product C), all containing the same
dose of the same drug, are given to a group of subjects in a
crossover study.
 Furthermore, suppose each product gave the values for AUC
indicated in below table.
 Data for Absolute and Relative Bioavailability

The F for Product B and Product C is 50% (F = 0.5) and 40% (F

= 0.4), respectively.
However, when the two oral products are compared, the
relative bioavailability of Product C as compared to Product B is
80%.
 FACTORS INFLUENCING BIOAVAILABILITY
 Before the therapeutic effect of an orally administered drug can be realized, the
drug must be absorbed.
 The systemic absorption of an orally administered drug in a solid dosage form is
comprised of three distinct steps:

1. Disintegration of the drug product

2. Dissolution of the drug in the fluids at the absorption site

3. Transfer of drug molecule across the membrane lining the gastrointestinal tract into
the systemic circulation.
 Any factor that affects any of these three steps can alter the drug’s bioavailability
and thereby its therapeutic effect.
 While there are more than three dozen of these factors that have been identified as
shown below.
 The various factors that can influence the bioavailability of a drug can be broadly
classified as dosage form-related or patient-related.
1. Bioavailability Factors related to the dosage form

2. Bioavailability Factors Related to the patient

Bioavailability and oral Dosage Forms
Factors influencing Gastric Emptying Rate
 Since drugs are generally administered to patients who are ill, it
is important to consider the effects of the disease process on
the bioavailability of the drug.
 Disease states, particularly those involving the GI tract, such as
celiac disease, Crohn’s disease, achlorhydria, and hypermotility
syndromes can certainly alter the absorption of a drug.
 In addition, some diseases concerning the cardiovascular
system and the liver may also alter circulating drug levels after
oral dosing.
 Drugs are frequently taken with food, and patients often use
mealtimes to remind them to take their medications.
 However, food can have a significant effect on the
bioavailability of drugs.

 The influence of food on drug absorption has been

recognized for some time, and several reviews have been

published on the influence of food on drug bioavailability.

 Food may influence drug absorption indirectly, through

physiological changes in the GI tract produced by the food,

and/or directly, through physical or chemical interactions

between the drug molecules and food components.

 When food is ingested, stomach emptying is delayed, gastric
secretions are increased, stomach pH is altered, and splanchnic
blood flow may increase.
 These may all affect bioavailability of drugs.
 Food may also interact directly with drugs, either chemically
(e.g. chelation) or physically, by adsorbing the drug or acting
as a barrier to absorption.
 In general, gastrointestinal absorption of drugs is favored by
an empty stomach, but the nature of drug-food interactions is
complex and unpredictable; drug absorption may be reduced,
delayed, enhanced or unaffected by the presence of food.
 Some effects of Food on Drug Absorption are here below:

 The volume of fluid with which an orally administered dose is taken can also
affect a drug’s bioavailability.
 Drug administration with a larger fluid volume will generally improve its
dissolution characteristics and may also result in more rapid stomach
emptying.
 Thus, more efficient and more reliable drug absorption can be expected
when an oral dosage form is administered with a larger volume of fluid.
 Interactions between drugs can have a significant effect on the bioavailability
of one or both drugs.

 Such interactions may be direct, as in chelation of tetracycline by polyvalent

metal ions in antacids or the adsorption of digoxin by cholestyramine resin, or
indirect, as with the increased rate of acetaminophen absorption due to the
increased gastric emptying rate produced by metoclopramide.

 Most of the reported drug-drug interactions have resulted in a reduction in the

rate and/or extent of drug absorption, the most frequent causes being
complexing of a drug with other substances, reduced GI motility and
alterations in drug ionization.

 An example of a direct interaction between drugs affecting bioavailability is the

interaction between iron and tetracycline.

 This is a well-documented and clinically significant interaction which can result

in a dramatic reduction in serum conc of tetracycline.
 METHODS OF ASSESSING BIOAVAILABILITY
 Bioavailability testing is a means of predicting the clinical efficacy of a drug;
the estimation of the bioavailability of a drug in a given dosage form is
direct evidence of the efficiency with which a dosage form performs its
intended therapeutic function.
 The bioavailability is fundamental to the goals of dosage form design and
essential for the clinical efficacy of the medication.
 Thus, bioavailability testing, which measures the rate and extent of drug
absorption, is a way to obtain evidence of the therapeutic utility of a drug
product.
 Bioavailability determinations are performed to ensure that a given drug
product will get the therapeutic agent to its site of action in an adequate
conc.
• Bioavailability studies are also carried out to compare the
availability of a drug substance from different dosage forms or
from the same dosage form produced by different
manufacturers.
• Bioavailability studies involve the administration of the test
dosage form to a panel of subjects, after which blood and/or urine
samples are collected and analyzed for drug content.
• Based on the concentration profile of the drug, a judgement is
made regarding the rate and extent of absorption of the drug.
• Normally, the study is conducted in a group of healthy, male
subjects who are of normal height and weight, and range in age
from 18 to 35 years
 1. IN-VIVO METHODS
 One method for assessing the bioavailability of a drug product is through the
demonstration of a clinically significant effect.
 However, such clinical studies are complex, expensive, time-consuming and
require a sensitive and quantitative measure of the desired response.
 Further, response is often quite variable, requiring a large test population.

 Practical considerations, therefore, preclude the use of this method except in

initial stages of development while proving the efficacy of a new chemical
entity.
 Quantification of pharmacologic effect is another possible way to assess a
drug’s bioavailability.
 This method is based on the assumption that a given intensity of response is
associated with a particular drug concentration at the site of action
 However, monitoring of pharmacologic data is often difficult, precision
and reproducibility are difficult to establish, and there are only a limited
number of pharmacologic effects (e.g. heart rate, body temperature,
blood sugar levels) that are applicable to this method.
 Because of these limitations, alternative methods have been developed
to predict the therapeutic potential of a drug.
 The current method to assess the clinical performance of a drug
involves measurement of the drug concentrations in the blood or urine.
 In such studies a single dose of the drug product is administered to a
panel of normal, healthy adult (18- to 35-year old) subjects.
 Blood and/or urine samples are collected over a period of time
following administration and are analyzed for drug content.
• Based on the blood concentration as a function of time and/or urinary excretion
profile, inferences are drawn regarding the rate and extent of absorption of the drug.

• These studies are relatively easy to conduct and require a limited number of
subjects.

1.1. Blood level studies

• Blood level studies are the most common type of human bioavailability studies, and
are based on the assumption that there is a direct relationship between the
concentration of drug in blood or plasma and the concentration of drug at the site of
action.

• By monitoring the concentration in the blood, it is thus possible to obtain an indirect

measure of drug response.

• Following the administration of a single dose of a medication, blood samples are

drawn at specific time intervals and analyzed for drug content.
 Plasma perfuses all the tissues of the body, including the
cellular elements in the blood.
 Assuming that a drug in the plasma is in dynamic
equilibrium with the tissues, then changes in the drug
concentration in plasma will reflect changes in tissue drug
concentrations.
 The key parameters to note are:
a. AUC-The area under the plasma
concentration-time curve.
• The AUC is proportional to the
total amount of drug reaching
the systemic circulation, and
thus characterizes the extent of
absorption.
b. Cmax , The maximum drug concentration. The maximum
concentration of drug in the plasma is a function of both the rate
and extent of absorption.
 Cmax will increase with an increase in the dose, as well as with an
increase in the absorption rate.
c. Tmax , The time at which the Cmax occurs. The Tmax reflects
the rate of drug absorption, and decreases as the absorption rate
increases.
• Bioavailability (the rate and extent of drug absorption) is generally
assessed by the determination of these three parameters.
• Since the AUC is representative of, and proportional to, the total
amount of drug absorbed into the circulation, it is used to quantitate
the extent of drug absorption.
1.2. Urinary Excretion Data
 Is an alternative bioavailability study measures the cumulative amount of
unchanged drug excreted in the urine.
 These studies involve collection of urine samples and the determination of
the total quantity of drug excreted in the urine as a function of time. These
studies are based on the premise that urinary excretion of the unchanged
drug is directly proportional to the plasma concentration of total drug.
 Thus, the total quantity of drug excreted in the urine is a reflection of the
quantity of drug absorbed from the gastrointestinal tract.
 Consider the following example: two products, A and B, each containing
100 mg of the same drug are administered orally. A total of 80 mg of drug
is recovered in the urine from Product A, but only 40 mg is recovered from
Product B.
 This indicates that twice as much drug was absorbed from Product A as
from Product B. (The fact that neither product resulted in excretion of the
entire dose might be due to the existence of other routes of elimination,
e.g. metabolism).
 Urinary excretion data are primarily useful for assessing extent of
drug absorption, although the time course for the cumulative
amount of drug excreted in the urine can also be used to estimate
the rate of absorption.
 In practice, these estimates are subject to a high degree of
variability, and are less reliable than those obtained from plasma
concentration-time profiles.
 Thus, urinary excretion of drug is not recommended as a
substitute for blood concentration data; rather, these studies
should be used in conjunction with blood level data for
confirmatory purposes.
 1.3. Single-dose versus Multiple-Dose
 Most bioavailability evaluations are made on the basis of single-dose administration.
 The argument has been made that single doses are not representative of the actual
clinical situation, since in most instances, patients require repeated administration of
a drug.
 When a drug is administered repeatedly at fixed intervals, with the dosing frequency
less than five half-lives, drug will accumulate in the body and eventually reach a
plateau, or a steady-state
 At steady-state, the amount of drug eliminated from the body during one dosing
interval is equal to the available dose (rate in = rate out); therefore, the AUC during a
dosing interval at steady-state is equal to the total area under the curve obtained
when a single dose is administered.
 This AUC can therefore be used to assess the extent of absorption of the drug, as well
as its absolute and relative bioavailability.
At steady state, the time required to eliminate one dose of drug is one dosing interval.
 When a drug obeys linear, first-order kinetics, it is possible to estimate the
results that would be obtained during multiple dosing from single-dose studies.
 Projection is easily made with regard to the extent of absorption, using the AUC
following a single dose.
 Results from bioequivalence studies indicate that conclusions on the extent of
absorption as assessed by the AUC can be made equally well on the basis of a
single or multiple dose study.
 In the case of drugs exhibiting nonlinear kinetics, establishing a linear
relationship between single- and multiple-dose bioavailability data has proven
to be a difficult task.
 Thus, it has been recommended that for drugs with either saturable
elimination or a nonlinear first-pass effect, steady-state studies be carried out
to assess their bioavailability.
2. IN-VITRO DISSOLUTION AND BIOAVAILABILITY
 A correlation between some physicochemical property of a
dosage form and the biological availability of the drug from
that dosage form is "in-vitro/in-vivo correlation".
 If such a correlation could be established, it would be possible
to use in-vitro data to predict a drug’s in-vivo bioavailability.
 This would drastically reduce, or in some cases, completely
eliminate the need for bioavailability tests.
 The desirability for this becomes clear when one considers the
cost and time involved in bioavailability studies as well as the
safety issues involved in administering drugs to healthy
subjects or patients.
 It would certainly be preferable to be able to substitute a
quick, inexpensive in-vitro test for in-vivo bioavailability
studies.
 This would be possible if in-vitro tests could reliably and
accurately predict drug absorption and reflect the in-vivo
performance of a drug in humans.
a. Disintegration Tests- The early attempts to establish an
indicator of drug bioavailability focused on disintegration as
the most pertinent in-vitro parameter.
 The first official disintegration test appeared in the United
States Pharmacopeia (USP) in 1950.
 However, while it is true that a solid dosage form must
disintegrate before significant dissolution and absorption can
occur, meeting the disintegration test requirement only
insures that the dosage form (tablet) will break up into
sufficiently small particles in a specified length of time.
 It does not ensure that the rate of solution of the drug is
adequate to produce suitable blood levels of the active
ingredient.
 Therefore, while the test for tablet disintegration is very
useful for quality control purposes in manufacturing, it is a
poor index of bioavailability.
b. Dissolution Tests- Since a drug must go into solution
before it can be absorbed, and since the rate at which a drug
dissolves from a dosage form often determines its rate
and/or extent of absorption, attention has been directed at
the dissolution rate.
 It is currently considered to be the most sensitive in-vitro
parameter most likely to correlate with bioavailability.
• There are two official USP dissolution methods: Apparatus 1,
(basket method), and Apparatus 2 (paddle method).
• Dissolution tests are an extremely valuable tool in ensuring
the quality of a drug product.
• Generally, product-to-product variations are due to
formulation factors, such as particle size differences,
excessive amounts of lubricant and coatings.
• These factors are reactive to dissolution testing.

• Thus, dissolution tests are very effective in discriminating

between and within batches of drug product(s).
• The dissolution test, in addition, can exclude definitively any
unacceptable product.
Limitations of dissolution tests
 There are, however, problems with in-vitro dissolution testing
which should be noted - problems which make correlation with in-
vivo availability difficult.
 The first is related to instrument variance and the absence of a
standard method.
 The tests described in the USP are but a few of the large number
of dissolution methods proposed to predict bioavailability.
 Since the dissolution rate of a dosage form is dependent on the
methodology used in the dissolution test, changes in the
apparatus, dissolution medium, etc., can dramatically modify the
results.
 Another significant problem is related to the difference between the in-
vitro and in-vivo environments in which dissolution occurs.
 In-vitro studies are generally carried out under controlled conditions in
one, or perhaps two, standardized solvents.
 The in-vivo environment (the GIT), on the other hand, is a continuously
changing, complex environment.
 There are many variables which can affect the dissolution rate of a drug
in the gastrointestinal tract, including pH, enzyme secretions, surface
tension, motility, presence of other substances and absorption surfaces.
 Thus, drugs frequently dissolve in the body at rates quite different from
those observed in an in-vitro test situation.
 Most of the official dissolution tests tend to be acceleration dissolution
tests which bear limited or no r/nship with in-vivo dissolution.
 Adding to the complexity of correlating dissolution with in-
vivo absorption are factors such as drug-drug interactions,
age, food effects, health, genetic background, biorhythm
and physical activity.
 All these factors may have an effect on the rate and extent
of absorption of a drug.
 Thus, the in-vivo environment is far more complex, variable,
and unpredictable than any in-vitro test environment,
making in-vitro / in-vivo correlations very difficult.
 A simple dissolution test in a standardized vehicle cannot
reflect the in vivo absorption of a drug across a population
3. In-vitro / In-vivo Correlation Studies
 Even if an in-vitro test could be designed that would
accurately reflect the dissolution process in the
gastrointestinal tract, dissolution is only one of many factors
that affect a drug’s bioavailability.
 For example, saturable presystemic metabolism may affect the
extent of drug absorption, but this would not be predicted by
an in-vitro test.
 Dissolution studies also would not predict poor bioavailability
due to instability in gastric fluid or complexation with another
drug or food component.
 Thus, the ultimate evaluation a drug product’s performance

under the conditions expected in clinical therapy must be an

in-vivo test; a dissolution test is unlikely to entirely replace

bioavailability testing.

 In-vitro methods are important in the development and

optimization of dosage forms while in-vivo tests are essential

in obtaining information on the behavior of medication in

living organisms.

 One cannot be substituted for the other.

 4. Bioequivalence

 "Bioequivalence" is a comparison of the bioavailability of two

or more drug products.

 Thus, two products or formulations containing the same

active ingredient are bioequivalent if their rates and extents
of absorption are the same.

 When a new formulation of an existing drug is developed, its

bioavailability is generally evaluated relative to the standard
formulation of the originator.
 Indeed, a bioequivalence trial against the standard formulation
is the key feature of an Abbreviated New Drug Application
(ANDA) submitted to the Food and Drug Administration by a
manufacturer who wishes to produce a generic drug.

 For a generic drug to be considered bioequivalent to a pioneer

product, there must be no statistical differences (as specified in
the accepted criteria) between their plasma concentration- time
profiles.

 Because two products rarely exhibit absolutely identical

profiles, some degree of difference must be considered
acceptable.
 Two products that are deemed to be bioequivalent are also
assumed to be therapeutically equivalent, and therefore
interchangeable.
 This principle is fundamental to the concept of bioequivalence
and is the basic premise on which it is founded.
 In general, the FDA considers two products to be "therapeutic
equivalents" if they each meet the following criteria:
1. They are pharmaceutical equivalents,
2. They are bioequivalent (demonstrated either by a
bioavailability measurement or an in vitro standard),
3. They are in compliance with compendial standards for strength,
quality, purity and identity,
4. They are adequately labelled, and
5. They have been manufactured in compliance with Good
Manufacturing Practices as established by the FDA.
 In order for a drug product to be interchangeable with the
pioneer (innovator or brand name) product, it must be both
pharmaceutically equivalent and bioequivalent to it.
 According to the FDA, "pharmaceutical equivalents" are drug
products that contain identical active ingredients and are
identical in strength or concentration, dosage form, and route
of administration.
 However, pharmaceutical equivalents do not necessarily
contain the same inactive ingredients; various manufacturers’
dosage forms may differ in color, flavor, shape, and
excipients.
 The terms "pharmaceutical equivalents" and "chemical
equivalents" are often used interchangeably.
• The drugs fall in three categories: "high," "moderate," or "low
risk“ based on the clinical implications by being related to the
therapeutic index of the drug, the dose of the drug and the
nature of the disease.
Drugs with various risk potential for in equivalence
 CHAPTER-4
BIOAVAILABILITY FROM OTHER ROUTES OF
ADMINISTRATION
 Bioavailability studies are performed for both approved active drug ingredients and
therapeutic moieties not yet approved for marketing by the FDA.

 New formulations of active drug ingredients must be approved by the FDA before
marketing.

 In approving a drug product for marketing, the FDA ensures that the drug product
is safe and effective for its labeled indications for use.

 Moreover, the drug product must meet all applicable standards of identity, strength,
quality, and purity.

 To ensure that these standards are met, the FDA requires

bioavailability/pharmacokinetic studies and, where necessary, bioequivalence studies
for all drug products (FDA Guidance for Industry, 2003).

 Bioavailability may be considered as one aspect of drug product quality that links in-
vivo performance of the drug product used in clinical trials to studies demonstrating
evidence of safety and efficacy.
Routes of administrations
4.1. Percutaneous Administration
 Transdermal permeation, or percutaneous absorption, can be
defined as the passage of a substance, such as a drug, from
the outside of the skin through its various layers into the
bloodstream.
 Any time there is systemic access of a drug, unwanted side
effects or toxic effects can occur.
 Certainly, each dosage form has its unique place in medicine,
but some attributes of the transdermal delivery system
provide distinct advantages over traditional methods.
The advantages of cutaneous drug delivery are:
 The system avoids the chemically hostile gastrointestinal (GI)
environment;
 No GI distress or other physiological contraindications of the oral route
exist;
 The system can provide adequate absorption of certain drugs; there is
increased patient compliance;
 The system avoids the first-pass effect;
 The system allows for the effective use of drugs with short biological
half-lives; the system allows for the administration of drugs with narrow
therapeutic windows;
 The system provides controlled plasma levels of highly potent drugs;
 Drug input can be promptly interrupted should toxicity occur.
Disadvantages of this system include:
 Drugs that require high blood levels cannot be administered;
 The adhesive used may not adhere well to all types of skin;

 Drug or drug formulation may cause skin irritation or

sensitization;
 The patches can be uncomfortable to wear; and
 This system may not be economical for some patients.
Factors influencing drug skin absorption:
 Patient age
 Application site

 State of hydration of the stratum corneum

 Thickness and intactness of the stratum corneum
 Physical characteristics of the solute

 Physical characteristics of the vehicle or solvent

 Skin structure and its properties,
 Transdermal delivery is a realistic option only for drugs
generally given in small doses (<10mg) and which have good
membrane penetration.
 Drugs currently approved for transdermal delivery include
clonidine, estradiol, nicotine, nitroglycerin, and scopolamine.
 The percutaneous absorption or the transdermal delivery of a
drug occurs in the following manner.
 Initially a topically applied drug is absorbed into the stratum
corneum and diffuses through that layer of skin into the
epidermis and then into the dermis where drug molecules
reach capillaries and enter the circulatory system.
 Diffusion through the stratum corneum is the rate-determining step
unless skin perfusion is decreased.
 If the latter case, diffusion is controlled by the transfer of drug
molecules into capillaries rather than by the diffusion process
previously explained.
 Drugs chosen for delivery via a transdermal drugdelivery system must
adequately penetrate the skin in such a way that the system
determines the delivery rate that should be fairly constant.
 In addition, the drug must not irritate or sensitize the skin.
 It is hoped that in the future more drugs will be developed for
transdermal delivery.
 This could become an alternative route for drug delivery to children
who have difficulty with oral administration.
4.2. Ophthalmic Administration
 Ocular drug delivery is administration of drug to eye to
circumvent its ailments.
 The different modalities of ocular administrations (topical,
subconjunctival, intravitreal) which are solutions, suspensions,
gels, ointments and inserts are almost exclusively intended for
delivery of drugs to treat local ophthalmic diseases.
 For topical ocular administration, liquid formulations composed
of solutions and suspensions are the most commonly applied
because they are easy to use and do not interfere with vision
 Problems with topical ophthalmic formulations are
ineffectiveness due to dilution in the tear film and the rapid
drainage into the nasolacrimal duct.
 Moreover, a proportion of the drug may be absorbed to the
systemic circulation across the conjunctiva.
 Therefore, conventional ophthalmic drug delivery system
suffer with the problems such as rapid precorneal
elimination; solution drainage by gravity; necessity of
frequent instillation; poor drainage of instilled solutions; tear
turnover; poor corneal permeability; nasolacrimal drainage;
systemic absorption; blurred vision; and conjunctival absorption.
 Ocular drug delivery has remained as one of the most challenging task
for pharmaceutical scientists.
 This is due to unique anatomy; physiology and biochemistry of the eye
restrict the entry of drug molecules at the required site of action.
 Especially; corneal, conjunctival epithelia, tear film, mucus layer of the
tear film assisted by frequent blinking entrap and serve as biological
barriers to debris, microorganisms and drugs.
 These are the main reasons that many drugs, especially large
hydrophobic molecules such as peptides, have difficulty in crossing the
ocular barrier and reaching the target tissues.
 Drug delivery systems that are able to overcome these barriers are
perceived as promising strategies to treat diseases affecting both the
anterior surfaces and the inner compartments of the eye.
  4.3. Rectal and vaginal Administration
 The vagina cannot be considered to be a route for the systemic
administration of drugs, although oestrogens for systemic
deliver have been applied intravaginally.
 Certain medicaments are, however, absorbed when applied to
the vaginal epithelium as it is permeable to a wide range of
substances including steroids, prostaglandins, iodine and some
antibiotics.
 Econazole and miconazole are also both appreciably absorbed.
in the vagina decreases after puberty, varying between pH 4 and
5 depending on the point in the menstrual cycle and also on
the location within the vagina, the pH being higher near the
cervix.
 The absorbing surface is under constant change, therefore
absorption is variable.
 While the presence of mucus is likely to retard absorption, there is
unlikely to be other material in the vagina which will inhibit absorption.
 The uterine and pudendal arteries are the main sources of blood to the
vagina; the venous plexus which surrounds the vagina empties into the
internal ileac veins.
 Lymph vessels drain the vagina, and vaginal capillaries are found in
close proximity to the basal epithelial layer.
 Proteins and peptides, particularly in the presence of absorption
enhancers, can be successfully administered by this route, although
surfactant-based enhancers are apparently not effective in the vagina.
 Vaginal enzymes, especially the proteases, are likely to present
problems in the vaginal delivery of proteins and peptides.
 Conventional vaginal delivery systems include vaginal tablets,
foams, gels, suspensions and pessaries.
 Vaginal rings have been developed to deliver contraceptive
steroids.
Rectal absorption of drugs
 Drugs administered by the rectal route in suppositories are
placed in intimate contact with the rectal mucosa, which
behaves as a normal lipoidal barrier.
 The pH in the rectal cavity lies between 7.2 and 7.4, but the
rectal fluids have little buffering capacity.
 As with topical medication, the formulation of the suppository
can have marked effects on the activity of the drug.
 Factors such as retention of the suppository for a sufficient
duration of time in the rectal cavity also influence the
outcome of therapy; the size and shape of the suppository
and its melting point may also determine bioavailability.
 Superior haemorrhoidal veins connect with the portal vein
and thus transport drugs absorbed in the upper part of the
rectal cavity to the liver; the inferior veins enter into the
inferior vena cava and thus bypass the liver.
 The particular venous route the drug takes is affected by the
extent to which the suppository migrates in its original or
molten form further up the gastrointestinal tract, and this
may be variable.
 The rectal route therefore does not necessarily, or even
reproducibly, avoid the liver metabolism before systemic etry
4.4. Inhalation therapy

 The respiratory system provides a route of entry into the body for a
variety of airborne substances but is also a route of medication.

 The large contact area of its surfaces extends to more than 30m 2.

 The surfaces have been described as ‘gossamer-thin membranes’ that

separate the lung air from the blood, which courses through some
2000 km of capillaries in the lungs.

 There is intimacy between the lung tissue and blood and the
atmospheric environment.

 The route is thus used for rapid relief of asthmatic conditions, where
both local and systemic effects are required, for chronic therapy and
for the administration of peptides and proteins.
 Orally administered corticosteroids are effective in the treatment of
chronic bronchial asthma.
 The inhalation route has been widely used in attempts to avoid
systemic side-effects, such as adrenal suppression, but evidence
suggests that inhaled steroids are absorbed systemically to a
significant extent.
 The respiratory tract epithelium has permeability characteristics
similar to those of the classical biological membrane, so lipid-soluble
compounds are absorbed more rapidly than lipid-insoluble molecules.
 Relative to the gastrointestinal mucosa the pulmonary epithelium
possesses a high permeability to water soluble molecules, which is an
advantage with drugs such as sodium cromoglicate.
 The drug is well absorbed from the lungs with a clearance
rate of about 1 hour even though the molecule is completely
ionised at physiological pH.
 The free acid is very insoluble in both polar and non-polar
solvents and has virtually no lipid solubility.
 Because of this, and the insolubility of the unionised form,
very little of an oral dose of sodium cromoglicate is
absorbed.
 Powder swallowed after inhalation therefore contributes little
to the systemic dose and is subsequently excreted in the
urine and bile.
 Drugs administered by inhalation are mostly intended to
have a direct effect on the lungs.
 However, the efficiency of inhalation therapy is often not
high because of the difficulty in targeting particles to the
sites of maximal absorption.
 The nasal route

 Two main classes of medicinal agents are applied by the

nasal route:
 Drugs for the alleviation of nasal symptoms
 Drugs that are inactivated in the gastrointestinal tract
following oral administration and where the route is an
alternative to injection, such as for peptides and
proteins
 Factors such as droplet or particle size which affect
deposition in the respiratory tract are involved if
administration is by aerosol, but formulations may also be
 The physiological condition of the nose, its vascularity, and
mucus flow rate are therefore of importance.
 So too is the formulation used – the volume, concentration,
viscosity, pH and tonicity of the applied medicament can
affect activity.
 As the condition of the nasal passages changes with changes
in the environment, temperature and humidity, it is clearly
not an ideal route for absorption of drugs or vaccines, but
may be the only feasible route for some agents.
4.5. Intra-muscular Administration
 The intramuscular route of administration have long been
regarded as efficient routes because it bypass the problems
encountered in the stomach and intestine, but not all the drug
injected will necessarily be bioavailable.
 In order for a drug to have a systemic action following injection,
it must be released from the formulation and reach the site of
action in sufficient amounts and at a sufficient rate to produce
the desired pharmacological effect.
 Drugs with the correct physicochemical characteristics can diffuse
through the tissue and pass across the capillary walls and thus
enter the circulation via the capillary supply.
 Both dissolution and diffusion are important parameters in
defining bioavailability of species by the i.m. or s.c. routes.
 Hydrophilic molecules will be transported to the blood after
diffusing through muscle fibers and then through the pores in the
capillary walls, being incapable of absorption through the lipid
walls.
 The transport through the capillary wall is the rate-limiting step in
most cases; the larger the molecule the more slowly it diffuses
and the greater difficulty it has in traversing the aqueous pore in
the capillary walls or the cell junction.
 The ‘pores’, of whatever character they are, account for only 1%
of the available surface of the capillary wall.
 CHAPTER-5
CLINICAL PHARMACOKINETICS

164
• After a drug is released from its dosage form, the drug is
absorbed into the surrounding tissue, the body, or both.
• The distribution through and elimination of the drug in the
body varies for each patient but can be characterized using
mathematical models and statistics.
• The description of drug distribution and elimination is often
termed drug disposition.
• Characterization of drug disposition is an important
prerequisite for determination or modification of dosing
regimens for individuals and groups of patients.

165
• Pharmacokinetics is defined as the study of rate processes involved in
absorption, distribution, metabolism and excretion (ADME).
• All the drug processes are occurring at a certain rate.
• Under the subject pharmacokinetics, we study those rates and built up
equations to predict those rate processes.
• The study of pharmacokinetics involves both experimental and theoretical
approaches.
• The experimental approach involves
1. The development of biological sampling techniques
2. Analytical methods development for the measurement of drugs and
metabolites
3. And the procedures for data collection and manipulation.
• The theoretical aspect of pharmacokinetics involves the development of
pharmacokinetic models that predicts drug disposition after drug
administration.
• The application of statistics is an integral part of pharmacokinetic models
top determine data errors, deviation of models and correlation.

166
Application of pharmacokinetics

1. The bioavailabilty of a dosage form is calculated by pharmacokinetic

equations.

2. The frequency of dosing is calculated from pharmacokinetic equations.

3. To calculate the dose of a controlled release dosage form

pharmacokinetic equations are required.

4. In case of patients with kidney failure the dose of a drug should be

calculated very cautiously.
 If the rate of absorption of the drug is greater than the elimination rate
of the drug from that patient then the drug will be accumulated in the
body and may show toxic effect.
 The rate of elimination of the drug from the body of that patient is
calculated with the help of pharmacokinetic equations. 167
5. When a potent anticancer drug is administered to a patient
the plasma concentration of the drug must be very close to
minimum effective concentration.
 Since the therapeutic index of the drug is very narrow in case
of potent drugs so rate of administration must also be very
slow.
 This rate of administration is calculated by PK principles.
Population pharmacokinetics is the study of
pharmacokinetic differences of drug in various population
groups.

168
Therapeutic drug monitoring (TDM)
 When drug with narrow therapeutic indices are used in patients, it is
necessary to monitor plasma drug concentration closely by taking periodic
blood samples.
 Some drugs those are frequently monitored are aminoglycoside antibiotics,
convulsants and anticancer drugs in order to minimize adverse side effects.
 Pharmacokinetics is applied to TDM for very potent drugs such as those
with a narrow therapeutic range, in order to optimize efficacy and to
prevent any adverse toxicity.
 For these drugs, it is necessary to monitor the patient, either by monitoring
plasma drug concentrations (eg, theophylline) or by monitoring a specific
pharmacodynamic endpoint such as prothrombin clotting time (eg,
warfarin).
169
Pharmacodynamics 
 Pharmacodynamics refers to the relationship between the drug
concentration at the site of action (receptor) and
pharmacologic response, including biochemical and physiologic
effects that influence the interaction of drug with the receptor.
 The interaction of a drug molecule with a receptor causes the
initiation of a sequence of molecular events resulting in a
pharmacologic or toxic response.
 Pharmacokinetic-pharmacodynamic models are constructed to
relate plasma drug level to drug concentration in the site of
action and establish the intensity and time course of the drug.
170
Toxicokinetics
 Toxicokinetics is the application of pk principles to the design,
conduct, and interpretation of drug safety evaluation studies
and in validating dose-related exposure in animals.
 Toxicokinetic data aids in the interpretation of toxicologic
findings in animals and extrapolation of the resulting data to
humans.
 Toxicokinetic studies are performed in animals during
preclinical drug development and may continue after the drug
has been tested in clinical trials.
 Clinical toxicology is the study of adverse effects of drugs and
toxic substances (poisons) in the body.
 The pks of a drug in an overmedicated (intoxicated) patient
may be very different from the pharmacokinetics of the same
drug given in lower therapeutic doses.
 Drugs frequently involved in toxicity cases include
acetaminophen, salicylates, morphine, and the tricylic 171
• Clinical pharmacokinetics is application of
pharmacokinetic concepts to maximize
patient treatment outcome and to reduces
potential side effects

172
Measurement of Drug Concentrations
 Because drug concentrations are an important element in
determining individual or population pks, drug concentrations
are measured in biologic samples, such as milk, saliva,
plasma, and urine.
 Sensitive, accurate, and precise analytical methods are
available for the direct measurement of drugs in biologic
matrices.
 Such measurements are generally validated so that accurate
information is generated for pharmacokinetic and clinical
monitoring.
 In general, chromatographic methods are most frequently
employed for drug concentration measurement, because
chromatography separates the drug from other related
materials that may cause assay interference.

173
Sampling of Biologic Specimens
 Only a few biologic specimens may be obtained safely from the
patient to gain information as to the drug concentration in the
body.
 Invasive methods include sampling blood, spinal fluid, synovial
fluid, tissue biopsy, or any biologic material that requires
parenteral or surgical intervention in the patient.
 In contrast, noninvasive methods include sampling of urine,
saliva, feces, expired air, or any biologic material that can be
obtained without parenteral or surgical intervention.
 The measurement of drug and metabolite concentration in each
of these biologic materials yields important information, such as
the amount of drug retained in, or transported into, that region
of the tissue or fluid, the likely pharmacologic or toxicologic
outcome of drug dosing, and drug metabolite formation or
transport.
174
Drug Concentrations in Blood, Plasma, or Serum
 Measurement of drug concentration (levels) in the blood, serum, or
plasma is the most direct approach to assessing the pharmacokinetics
of the drug in the body.
 Whole blood contains cellular elements including red blood cells, white
blood cells, platelets, and various other proteins, such as albumin and
globulins.
 In general, serum or plasma is most commonly used for drug
measurement.
 To obtain serum, whole blood is allowed to clot and the serum is
collected from the supernatant after centrifugation.
 Plasma is obtained from the supernatant of centrifuged whole blood to
which an anticoagulant, such as heparin, has been added.
 Therefore, the protein content of serum and plasma is not the same.
 Plasma perfuses all the tissues of the body, including the cellular
elements in the blood.
 Assuming that a drug in the plasma is in dynamic equilibrium with the
tissues, then changes in the drug concentration in plasma will reflect
changes in tissue drug concentrations. 175
 The four PK processes
 Determine the conc of a drug at its sites of action
 Involve drug mov’t—across biological membranes
 Their performance is measured by PK parameters
Basic PK parameters/principles/variables/terms:
 Derived from the measurement of drug conc in blood or
plasma
 Bioavailability, F
 Apparent Volume of distribution, Vd
 Clearance, Cl
 Half- life, T1/2
 Elimination constant, K 176
Plasma Level–Time Curve
 The plasma level–time curve is generated by obtaining the
drug concentration in plasma samples taken at various time
intervals after a drug product is administered.
 The concentration of drug in each plasma sample is plotted
on rectangular-coordinate graph paper against the
corresponding time at which the plasma sample was
removed.
 As the drug reaches the general (systemic) circulation,
plasma drug concentrations will rise up to a maximum.
 Usually, absorption of a drug is more rapid than elimination.
 As the drug is being absorbed into the systemic circulation,
the drug is distributed to all the tissues in the body and is
also simultaneously being eliminated.
 Elimination of a drug can proceed by excretion,
biotransformation, or a combination of both. 177
 The relationship of the drug level–time curve and various pharmacologic
parameters for the drug is shown in .
 MEC and MTC represent the minimum effective concentration and
minimum toxic concentration of drug, respectively.
 For some drugs, such as those acting on the autonomic nervous system, it
is useful to know the concentration of drug that will just barely produce a
pharmacologic effect (ie, MEC).
 Assuming the drug concentration in the plasma is in equilibrium with the
tissues, the MEC reflects the minimum concentration of drug needed at
the receptors to produce the desired pharmacologic effect.
 Similarly, the MTC represents the drug concentration needed to just barely
produce a toxic effect.
 The onset time corresponds to the time required for the drug to reach the
MEC.
 The intensity of the pharmacologic effect is proportional to the number of
drug receptors occupied, which is reflected in the observation that higher
plasma drug concentrations produce a greater pharmacologic response, up
to a maximum.
 The duration of drug action is the difference between the onset time and
the time for the drug to decline back to the MEC. 178
Generalized plasma level–time curve after oral administration of a drug.

179
 In contrast, the pharmacokineticist can also describe the plasma
level–time curve in terms of such pharmacokinetic terms as peak
plasma level, time for peak plasma level, and area under the
curve, or AUC.
 The time of peak plasma level is the time of maximum drug
concentration in the plasma and is a rough marker of average
rate of drug absorption.
 The peak plasma level or maximum drug concentration is related
to the dose, the rate constant for absorption, and the elimination
constant of the drug.
 The AUC is related to the amount of drug absorbed systemically.
180
Plasma level–time curve showing peak time and concentration. The
shaded portion represents the AUC (area under the curve).

181
Plasma level- time curve Parameters are:
1. Minimum effective conc, MEC- The minimum conc of drug needed
at the receptors to produce the desired pharmacologic effect.
2. Minimum toxic conc, MTC- The drug conc needed to just produce a
toxic effect.
3. Onset time- The time required for the drug to reach the MEC.
4. Duration of action- The difference between the onset time and the
time for the drug to decline back to the MEC.
5. Tmax- The time of maximum drug conc in the plasma.
Proportional to the rate of drug absorption
6. Cmax- The maximum drug serum conc. Related to the dose & the
rate constants for absorption and elimination of the drug.
7. Area under plasma conc vs. time curve, AUC- The total exposure
of the drug. Related to the amount of drug absorbed systemically.

182
Drug Concentrations in Tissues
 Tissue biopsies are occasionally removed for diagnostic
purposes, such as the verification of a malignancy.
 Usually, only a small sample of tissue is removed, making drug
concentration measurement difficult.
 Drug concentrations in tissue biopsies may not reflect drug
concentration in other tissues nor the drug concentration in all
parts of the tissue from which the biopsy material was
removed.
 For example, if the tissue biopsy was for the diagnosis of a
tumor within the tissue, the blood flow to the tumor cells may
not be the same as the blood flow to other cells in this tissue.
 In fact, for many tissues, blood flow to one part of the tissues
need not be the same as the blood flow to another part of the
same tissue.
 The measurement of the drug concentration in tissue biopsy
material may be used to ascertain if the drug reached the 183
Drug Concentrations in Urine and Feces
 Measurement of drug in urine is an indirect method to ascertain the
bioavailability of a drug.
 The rate and extent of drug excreted in the urine reflects the rate and
extent of systemic drug absorption.
 The use of urinary drug excretion measurements to establish various
pharmacokinetic parameters is discussed in .
 Measurement of drug in feces may reflect drug that has not been
absorbed after an oral dose or may reflect drug that has been expelled
by biliary secretion after systemic absorption.
 Fecal drug excretion is often performed in mass balance studies, in
which the investigator attempts to account for the entire dose given to
the patient.
 For a mass balance study, both urine and feces are collected and their
drug content measured.
 For certain solid oral dosage forms that do not dissolve in the GIT but
slowly leach out drug, fecal collection is performed to recover the
dosage form.
 The undissolved dosage form is then assayed for residual drug. 184
Drug Concentrations in Saliva
 Saliva drug concentrations have been reviewed for many drugs
for therapeutic drug monitoring.
 Because only free drug diffuses into the saliva, saliva drug
levels tend to approximate free drug rather than total plasma
drug concentration.
 The saliva drug conc ratio is less than 1 for many drugs.
 The saliva/plasma drug conc ratio is mostly influenced by the
pKa of the drug and the pH of the saliva.
 Weak acid drugs and weak base drugs with pKa significantly
different than pH 7.4 (plasma pH) generally have better
correlation to plasma drug levels.
 The saliva drug conc taken after equilibrium with the plasma
drug concentration generally provide more stable indication of
drug levels in the body.
 The use of salivary drug conc as a therapeutic indicator should
be used with caution and preferably as a secondary indicator.185
Forensic Drug Measurements
 Forensic science is the application of science to personal injury,
murder, and other legal proceedings.
 Drug measurements in tissues obtained at autopsy or in other
bodily fluids such as saliva, urine, and blood may be useful if a
suspect or victim has taken an overdose of a legal medication, has
been poisoned, or has been using drugs of abuse such as opiates
(eg, heroin), cocaine, or marijuana.
 The appearance of social drugs in blood, urine, and saliva drug
analysis shows short-term drug abuse.
 These drugs may be eliminated rapidly, making it more difficult to
prove that the subject has been using drugs of abuse.
 The analysis for drugs of abuse in hair samples by very sensitive
assay methods, such as gas chromatography coupled with mass
spectrometry, provides information regarding past drug exposure.
 A study by showed that the hair samples from subjects who were
known drug abusers contained cocaine and 6-acetylmorphine, a
metabolite of heroine (diacetylmorphine). 186
 The study of PK s involves both experimental and theoretical
approaches.
 The experimental aspect of PK s involves the development of
biologic sampling techniques, analytical methods for the
measurement of drugs and metabolites, and procedures that
facilitate data collection and manipulation.
 The theoretical aspect of PK s involves the development of PK
models that predict drug disposition after drug administration.
 Statistical methods are used for PK parameter estimation and
data interpretation ultimately for the purpose of designing and
predicting optimal dosing regimens for individuals or groups of
patients. 187
 Statistical methods are applied to PK models to determine
data error and structural model deviations.
 Mathematics and computer techniques form the theoretical
basis of many PK methods.
 Classical PK s is a study of theoretical models focusing mostly
on model development and parameterization.
 Clinical PKs is the application of PK methods to drug therapy.

 Clinical PKs involves a multidisciplinary approach to

individually optimized dosing strategies based on the patient's
disease state and patient-specific considerations.

188
 CPK applies PK concepts & principles in the therapeutic mgt of pts
 It help to design individualized dosage regimens
 Primary goals of CPK
 To maximize drug benefits & in an individual pt
 To minimize chance of ADRs
 By using or applying PK principles
 Correlates b/n drug conc & their pharmacologic responses in the
actual pts
 To achieve successful drug therapy by optimally balancing the
desirable and the undesirable effects
 Application of PK principles to the safe and effective therapeutic
mgt of drugs in an individual patient.

189
 It involves a multidisciplinary approach to individually
optimized dosing strategies based on the patient‘s:
 Age
 Wt
 Gender
 Disease state
 Genetic variability
 Nutritional status
 Result in PK differences that affect the outcome of drug
therapy
• The study of PK differences of drugs in various population
groups- population PK 190
 Advantage of CPK study
1. Individualize patient drug therapy
2. Monitor medications with a narrow therapeutic index—TDM
3. Drugs that show steep conc-response curve
4. Decrease the risk of ADRs while maximizing pharmacologic
response of medications
5. As a diagnostic tool for underlying disease states
 Intra-& inter-individual variations will result in either:
– Subtherapeutic or
– Toxic response
 Require dosage adjustment

191
 A basic tenet of CPK is that the magnitudes of both the
desired response and toxicity are functions of drug conc at
site(s) of action
 Therapeutic failure results when:
– Too low conc- ineffective therapy, or
– Too high conc- unacceptable toxicity
 B/n these limits of conc- there is therapeutic
success/window.
 An optimal dosage regimen maintains Cp of a drug with in the
therapeutic window.
 Monitoring of plasma drug concentrations allows for the
adjustment of the drug dosage in order to individualize and
optimize therapeutic drug regimens.

192
193
Significance of Measuring Plasma Drug Concentrations
 The intensity of the pharmacologic or toxic effect of a drug is
often related to the concentration of the drug at the receptor
site, usually located in the tissue cells.
 Because most of the tissue cells are richly perfused with tissue
fluids or plasma, measuring the plasma drug level is a
responsive method of monitoring the course of therapy.
 Clinically, individual variations in the pharmacokinetics of drugs
are quite common.
 Monitoring the concentration of drugs in the blood or plasma
ascertains that the calculated dose actually delivers the plasma
level required for therapeutic effect.

194
 With some drugs, receptor expression and/or sensitivity in
individuals varies, so monitoring of plasma levels is needed
to distinguish the patient who is receiving too much of a drug
from the patient who is supersensitive to the drug.
 Moreover, the patient's physiologic functions may be affected
by disease, nutrition, environment, concurrent drug therapy,
and other factors.
 Pharmacokinetic models allow more accurate interpretation
of the relationship between plasma drug levels and
pharmacologic response.
 CHAPTER-6

DRUG ABSORPTION -ZERO ORDER

AND FIRST ORDER (1 HRS)
 For oral dosing, such factors as surface area of the GI tract,
stomach-emptying rate, GI mobility, and blood flow to the
absorption site all affect the rate and the extent of drug
absorption.
 In pharmacokinetics, the overall rate of drug absorption may
be described as either a first-order or zero-order input process.
 Most pharmacokinetic models assume first-order absorption
unless an assumption of zero-order absorption improves the
model significantly or has been verified experimentally.
 The rate of change in the amount of drug in the body, dD B/dt,
is dependent on the relative rates of drug absorption and
elimination.
 The net rate of drug accumulation in the body at any time is
equal to the rate of drug absorption minus the rate of drug
elimination, regardless of whether absorption is zero-order or
first-order.
 Model of drug absorption and elimination

 Where D GI is amount of drug in the gastrointestinal tract and D

E is amount of drug eliminated.

 A plasma level–time curve showing drug adsorption and

elimination rate processes is given in .
 During the absorption phase of a plasma level–time curve , the
rate of drug absorption is greater than the rate of drug
elimination.
 Note that during the absorption phase, elimination occurs
whenever drug is present in the plasma, even though
absorption predominates.
 Plasma level–time curve for a drug given in a
single oral dose. The drug absorption and
elimination phases of the curve are shown.

Zero-Order Absorption Model

 Zero-order drug absorption from the dosing site into the plasma usually
occurs when either the drug is absorbed by a saturable process or a zero-
order controlled-release delivery system is used.
 In this model, drug in the gastrointestinal tract, D GI, is absorbed
systemically at a constant rate, k 0.
 Drug is simultaneously and immediately eliminated from the body by a first-
order rate process defined by a first-order rate constant, k.
 This model is analogous to that of the administration of a drug by
intravenous infusion
 The rate of drug absorption is constant until the amount of drug in
the gut, D GI, is depleted.
 The time for complete drug absorption to occur is equal to D GI/k 0.
After this time, the drug is no longer available for absorption from
the gut.
 The drug concentration in the plasma subsequently declines in
accordance with a first-order elimination rate process.
First-Order Absorption Model
 Although zero-order absorption can occur, absorption is usually
assumed to be a first-order process.
 This model assumes a first-order input across the gut wall and
first-order elimination from the body.
 This model applies mostly to the oral absorption of drugs in
solution or rapidly dissolving dosage (immediate release) forms
such as tablets, capsules, and suppositories.
 In addition, drugs given by intramuscular or subcutaneous
aqueous injections may also be described using a first-order
process.
 For most drugs (those following first-order elimination) a
straight line can describe the change in natural log of plasma
concentration over time.
 Recognizing this relationship, we can now develop
mathematical methods to predict drug concentrations.
 For first-order processes, the rate of elimination (expressed as
the fraction of drug in the body removed over a unit of time) is
the same at high or low concentrations and is therefore called
an elimination rate constant.
 When drug elimination is first order, the negative slope of the
natural log of drug concentration versus time plot equals the drug's
elimination rate constant: slope =-elimination rate constant.
 Remember that the elimination rate constant is the fraction
of drug removed over a unit of time.
 If the elimination rate constant is 0.25 hr-1, then 25% of the
drug remaining in the body is removed each hour.
 Because we know that a plot of the natural log of drug
concentration over time is a straight line for a drug following
first-order elimination, we can predict drug concentrations for
any time after the dose if we know the equation for this line.
 The concepts presented in this lesson can be used to predict
plasma concentrations in some situations.
 For example, if a patient with renal dysfunction received a dose of
vancomycin and plasma concentrations were determined at 24 and
48 hours after the dose, then two plasma concentrations could be
plotted on semilog paper to determine when the concentration
would reach 10 mg/L . This information can be used to determine
when the next dose should be given.
 If elimination rate constant is 0.15 hr-1, this means that 15% of the
drug remaining in the body is removed each hour, so an initial
plasma concentration of 10 mg/L will decrease 15% (0.15 × 10
mg/L = 1.5 mg/L) to 8.5 mg/L by the end of the first hour.
 By the end of the second hour, the concentration will be 7.2 mg/L,
a 15% reduction from 8.5 mg/L (0.15 × 8.5 mg/L = 1.3).
 If we know that the plasma drug concentration just after a
gentamicin dose is 8 mg/L and the patient's elimination rate
constant is 0.25 hr-1, predict what the concentration will be 8
hours later:
HALF-LIFE
• Another important parameter that relates to the rate of drug
elimination is half-life (T1/2).
• The halflife is the time necessary for the concentration of drug in
the plasma to decrease by half.
• A drug's half-life is often related to its duration of action and also
may indicate when another dose should be given.
• One way to estimate the half-life is to visually examine the natural
log of plasma drug concentration versus time plot and note the
time required for the plasma concentration to decrease by half.
 The equation represents the important relationship between the
half-life and the elimination rate constant shown by mathematical
manipulation.
 Note that drug effects may persist for a period of time longer than
would be predicted by a drug's half-life.
 The greater the value of the half-life, the longer the drug stays in
the body.
• For example the decrease from 10 to 5 mg/L may takes approximately
1.5 hours.
• It also takes 1.5 hours for the concentration to decrease from 5.0 to 2.5
mg/L, from 7.0 to 3.5 mg/L, etc.
• At any point, the decrease in concentration by half takes approximately
1.5 hours, even when the decrease is from a concentration as low as 0.05
to 0.025 mg/L.
• Thus, the half-life can be estimated to be 1.5 hours.
• The half-life and the elimination rate constant express the same idea.
They indicate how quickly a drug is removed from the plasma and,
therefore, how often a dose has to be administered.
• If the half-life and peak plasma concentration of a drug are known, then
the plasma drug concentration at any time can be estimated.
• For example, if the peak plasma concentration is 100 mg/L after an
intravenous dose of a drug with a 2-hour half-life, then the concentration
will be 50 mg/L 2 hours after the peak concentration (a decrease by half).
• At 4 hours after the peak concentration, it will have decreased by half
again, to 25 mg/L, and so on
• The half-life and elimination rate constant is important in
determining drug dosages and dosing intervals.
• Note that drug effects may persist for a period of time longer than
would be predicted by a drug's half-life.
• The greater the value of the half-life, the longer the drug stays in
the body.
• The time between administration of doses is the dosing interval.
The dosing interval, symbolized by the Greek letter tau (t), is
determined by a drug's half-life.
• Rapidly eliminated drugs (i.e., those having a short half-life)
generally have to be given more frequently (shorter t), than drugs
with a longer half-life.
2. Zero order
 Zero-order drug absorption from the dosing site into the
plasma usually occurs when either the drug is absorbed by a
saturable process or controlled-release delivery system is used.
 The pharmacokinetic model assuming zero-order absorption is
described in this model, such drugs will be absorbed
systemically at a constant rate, k 0.

 Drug is simultaneously and immediately eliminated from the

body by a zero-order rate process defined by a zero-order rate
constant, k 0.

 This model is analogous to that of the administration of a drug

 In a zero-order reaction the rate of elimination is
independent of the concentration of the reactants, i.e. the
rate is constant.
 A constant rate of drug elimination from a body is highly
desirable.
 Zero-order kinetics often apply to processes occurring at
phase boundaries, where the concentration at the surface
remains constant either because elimination sites are
saturated (enzyme kinetics, drug receptor interaction) or are
constantly replenished by diffusion of fresh material from
within the bulk of one phase.
Lag Time
 In some individuals, absorption of drug after a single oral dose
does not start immediately, due to such physiologic factors as
stomach-emptying time and intestinal motility.
 The time delay prior to the commencement of first-order drug
absorption is known as lag time.
 The lag time, t 0, represents the beginning of drug absorption
and should not be confused with the pharmacologic term onset
time, which represents latency, eg, the time required for the
drug to reach minimum effective concentration.
Significance of Absorption Rate Constants
 The overall rate of systemic drug absorption from an orally
administered solid dosage form encompasses many individual
rate processes, including dissolution of the drug, GI motility,
blood flow, and transport of the drug across the capillary
membranes and into the systemic circulation.
 The rate of drug absorption represents the net result of all
these processes.
 The selection of a model with either first-order or zero-order
absorption is generally empirical.
 The actual drug absorption process may be zero-order, first-
order, or a combination of rate processes that is not easily
quantitated.
 For many immediate-release dosage forms, the absorption
process is first-order due to the physical nature of drug
diffusion.
 For certain controlled-release drug products, the rate of drug
absorption may be more appropriately described by a zero-
order rate constant.
 The calculation of k a is useful in designing a multiple-dosage
regimen.
 Knowledge of the k a and k allows for the prediction of peak
and trough plasma drug concentrations following multiple
dosing.
 In bioequivalence studies, drug products are given in
chemically equivalent doses, and the respective rates of
systemic absorption may not differ markedly.
 Therefore, for these studies, t max, or time of peak drug conc,
can be very useful in comparing the respective rates of
absorption of a drug from chemically equivalent drug products.
 CHAPTER-7

DISTRIBUTION (2 HRS)
 Once a drug begins to be absorbed, it undergoes various
transport processes, which deliver it to body areas away
from the absorption site.
 These transport processes are collectively referred to as
drug distribution and are evidenced by the changing
concentrations of drug in various body tissues and fluids.
 Information concerning the concentration of a drug in body
tissues and fluids is limited to only a few instances in time
(i.e., we know the precise plasma drug concentration only at
the few times that blood samples are drawn).
 Usually, we only measure plasma concentrations of drug,
recognizing that the drug can be present in many body
tissues.
 For most drugs, distribution throughout the body occurs
mainly by blood flow through organs and tissues.
• However, many factors can affect distribution, including:
 differing characteristics of body tissues,
 disease states that alter physiology,
 lipid solubility of the drug,
 Regional differences in physiologic pH (e.g., stomach and urine),
 Extent of protein binding of the drug.
1. BODY TISSUE CHARACTERISTICS
• To understand the distribution of a drug, the characteristics of
different tissues must be considered.
• Certain organs, such as the heart, lungs, and kidneys, are highly
perfused with blood; fat tissue and bone (not the marrow) are
much less perfused.
• Skeletal muscle is intermediate in blood perfusion.
• The importance of these differences in perfusion is that for most
drugs the rate of delivery from the circulation to a particular tissue
depends greatly on the blood flow to that tissue.
• This is called perfusion-limited distribution.
 The rate-limiting step is how quickly the drug gets to the tissue. If the blood
flow rate increases, the distribution of the drug to the tissue increases.
 Therefore, drugs apparently distribute more rapidly to areas with higher
blood flow.
 Highly perfused organs rapidly attain drug concentrations approaching those
in the plasma; less well-perfused tissues take more time to attain such
concentrations.
 Furthermore, certain anatomic barriers inhibit distribution, a concept
referred to as permeability-limited distribution.
 This situation occurs for polar drugs diffusing across tightly knit lipoidal
membranes.
 It is also influenced by the oil/water partition coefficient and degree of
ionization of a drug.
 Eg. the blood-brain barrier limits the amount of drug entering
the central nervous system from the bloodstream.
 This limitation is especially great for highly ionized drugs and
for those with large molecular weights.
 After a drug begins to distribute to tissue, the concentration in
tissue increases until it reaches an equilibrium at which the
amounts of drug entering and leaving the tissue are the same.
 The drug concentration in a tissue at equilibrium depends on
the plasma drug concentration and the rate at which drug
distributes into that tissue.
 In highly perfused organs, such as the liver, the distribution
rate is relatively high; for most agents, the drug in that tissue
rapidly equilibrates with the drug in plasma.
 For tissues in which the distribution rate is lower (e.g., fat),
reaching equilibrium may take much longer
2. DISEASE STATES AFFECTING DISTRIBUTION
 Another major factor affecting drug distribution is the effect of
various disease states on body physiology.
 In several disease states, such as liver, heart, and renal failure,
the cardiac output and/or perfusion of blood to various tissues
are altered.
 A decrease in perfusion to the tissues results in a lower rate of
distribution and, therefore, a lower drug concentration in the
affected tissues relative to the plasma drug concentration.
 When the tissue that receives poor perfusion is the primary
eliminating organ, a lower rate of drug elimination results, which
then may cause drug accumulation in the body.
3. LIPID SOLUBILITY OF THE DRUG
 The extent of drug distribution in tissues also depends on the
physiochemical properties of the drug as well as the
physiologic functions of the body.
 A drug that is highly lipid soluble easily penetrates most
membrane barriers, which are mainly lipid based, and
distributes extensively to fat tissues.
 Drugs that are very polar and therefore hydrophilic (e.g.,
aminoglycosides) do not distribute well into fat tissues.
 This difference becomes important when determining loading
dosage requirements of drugs in overweight patients.
 If total body weight is used to estimate dosage requirements
and the drug does not distribute to adipose tissue, the dose
can be overestimated.
• In general, volume of distribution is based on ideal body weight for
drugs that do not distribute well into adipose tissue and on total body
weight for drugs that do.
• If a drug distributes partially into fat, an adjusted body weight
between the patient's actual and ideal body weights is often used.
• The volume of distribution is dependent on the volume of the plasma
(3-5 L), the volume of the tissue, the fraction of unbound drug in the
plasma, and the fraction of unbound drug in the tissue.
• A drug must have a distribution at least as large as the volume of
plasma.
• The volume of the tissue is much more difficult to estimate.
4. REGIONAL DIFFERENCES IN PHYSIOLOGIC PH
• Another factor affecting drug distribution is the different physiologic
pHs of various areas of the body.
• The difference in pH can lead to localization of drug in tissues and
fluids.
• A drug that is predominantly in its ionized state at physiologic pH
(7.4) does not readily cross membrane barriers. and probably has a
limited distribution.
 An example of this phenomenon is excretion of drugs in breast
milk.
 Only un-ionized drug can pass through lipid membrane barriers
into breast milk.
 Alkaline drugs, which would be mostly un-ionized at pH 7.4,
pass into breast tissue.
 Once in breast tissue, the alkaline drugs ionize because breast
tissue has an acidic pH; therefore, the drugs become trapped in
this tissue.
 This same phenomenon can occur in the urine.
 Due to the nature of biologic membranes, drugs that are un-
ionized (uncharged) and have lipophilic (fat-soluble) properties
are more likely to cross most membrane barriers.
 Several drugs (e.g., amphotericin) are formulated in a lipid
emulsion to deliver the active drug to its intended site while
decreasing toxicity to other tissues.
4. PROTEIN BINDING
 Another factor that influences the distribution of drugs is
binding to tissues (nucleic acids, ligands, calcified tissues, and
adenosine triphosphatase) or proteins (albumins, globulins,
alpha-1-acid glycoprotein, and lipoproteins).
 It is the unbound or free portion of a drug that diffuses out of
plasma.
 Protein binding in plasma can range from 0 to >99% of the
total drug in the plasma and varies with different drugs.
 The extent of protein binding may depend on the presence of
other protein-bound drugs and the concentrations of drug and
proteins in the plasma.
 Although only unbound drug distributes freely, drug binding is
rapidly reversible (with few exceptions), so some portion is
always available as free drug for distribution.
 The association and dissociation process between the bound
and unbound states is very rapid and, we assume, continuous
 A drug's protein-binding characteristics depend on its physical and
chemical properties.
 Hydrophobic drugs usually associate with plasma proteins.
 The binding of a drug to plasma proteins will primarily be a
function of the affinity of the protein for the drug.
 The percentage of protein binding of a drug in plasma can be
determined experimentally as follows:
 where [total] is the total plasma drug concentration (unbound
drug + bound drug) and [unbound] refers to the unbound or free
plasma drug concentration.
 Although only the unbound portion of drug exerts its
pharmacologic effect, most drug assays measure total drug
concentration both bound and unbound drug.
 Therefore, changes in the binding characteristics of a drug could
affect pharmacologic response to the drug.
 For example, the anticonvulsant and toxic effects of phenytoin are
more closely related to the concentration of free drug in plasma
than to the concentration of total drug in plasma.
• The plasma concentration of the two major plasma-binding proteins,
albumin and alpha-1-acid glycoprotein, are known to be influenced b
various disease states.
• Obviously, such changes could have a significant impact on the plasma
protein binding of many drugs.
• For certain drugs that are highly protein bound and have a narrow
therapeutic index, it may be useful to obtain an unbound plasma drug
concentration rather than a total plasma drug concentration.
• This will more accurately reflect the true concentration of active drug.
An example of this is phenytoin.
• Warfarin, salicylates, and phenytoin are highly protein bound agents.
• Protein binding is certainly an important consideration in the
interpretation of plasma drug concentration data.
• However, a considerable amount of intra- and interpatient variability
exists in the plasma concentration of binding proteins (albumin and
alpha-1-acid glycoprotein) as well as their affinity for a specific drug.
• A major contributor to this variability is the presence of a disease or
altered physiologic state, which can affect the plasma concentration or
affinity of the binding protein.
• For example, albumin concentrations are decreased with
hepatic or renal dysfunction, and alpha-1-acid glycoprotein
concentrations are increased with myocardial infarction.
Renal dysfunction may also decrease the affinity of albumin
for phenytoin.
• In addition, concomitant administration of a displacer drug
(i.e., an agent that competes with the drug of interest for
common protein binding sites) can alter the protein binding
of a drug.
• Examples of displacer drugs include salicylic acid and
valproic acid.
• Changes in plasma protein binding of drugs can have considerable
influence on therapeutic or toxic effects that result from a drug
regimen.
• Changes in plasma and tissue protein binding can have a major
influence on clearance and volume of distribution.
• The consequence of protein binding changes on volume of drug
distribution was implied in this equation:

• The unbound fraction in the plasma and tissue is dependent on

both the quantity (concentration) and quality (affinity) of the
binding proteins; therefore, changes in these parameters can alter
the volume of distribution.
• increase in the unbound fraction in the plasma would result in an
increase in a drug's volume of distribution and result in a lower
plasma drug concentration.
 The extent of protein binding some time does not consistently
predict tissue distribution or half-life.
 In other words, because an agent has a high fraction bound
to protein does not mean it achieves poor tissue penetration.
 The volume of distribution is an important parameter for
determining proper drug dosing regimens.
 Often referred to as the apparent volume of distribution, it
does not have an exact physiologic significance, but it can
indicate the extent of drug distribution and aid in
determination of dosage requirements.
 Generally, dosing is proportional to the volume of distribution.
 For example: the larger the volume of distribution, the larger
a dose must be to achieve a desired target concentration.
 The fluid portion (water) in an adult makes up
approximately 60% of total body weight and is composed of
intracellular fluid (35%) and extracellular fluid (25%).
 Extracellular fluid is made up of plasma (4%) and interstitial
fluid (21%).
 Volume of distribution (V) is an important indicator of the
extent of drug distribution into body fluids and tissues.
 V relates the amount of drug in the body (X) to the
measured concentration in the plasma (C).
 Thus, V is the volume required to account for all of the
drug in the body if the concentrations in all tissues are
the same as the plasma concentration:
 A large volume of distribution usually indicates that the
drug distributes extensively into body tissues and fluids.
 Conversely, a small volume of distribution often indicates
limited drug distribution.
 Volume of distribution indicates the extent of distribution but
not the tissues or fluids into which the drug is distributing.
 Two drugs can have the same volume of distribution, but one
may distribute primarily into muscle tissues, whereas the other
may concentrate in adipose tissues.
 When V is many times the volume of the body, the drug concs
in some tissues should be much greater than those in plasma.
 The smallest volume in which a drug may distribute is the
plasma volume.
 As with other pharmacokinetic parameters, volume of
distribution can vary considerably from one person to another
because of differences in physiology or disease states.
 Something to note: the dose of a drug (X0) and the amount of
drug in the body (X) are essentially the same thing because all
of the dose goes into the body.
 If a drug has a volume of distribution of approximately 15-18 L in a
70-kg person, we might assume that its distribution is limited to
extracellular fluid, as that is the approximate volume of
extracellular fluid in the body.
 If a drug has a volume of distribution of about 40 L, the drug may
be distributing into all body water, because a 70-kg person has
approximately 40 L of body water (70kg × 60%).
 If the volume of distribution is much greater than 40-50 L, the drug
probably is being concentrated in tissue outside the plasma and
interstitial fluid.
 If a drug distributes extensively into tissues, the volume of
distribution calculated from plasma concentrations could be much
higher than the actual physiologic volume in which it distributes.
 For example, by measuring plasma concentrations, it appears that
digoxin distributes in approximately 440 L in an adult.
 Because digoxin binds extensively to muscle tissue, plasma levels
are fairly low relative to concentrations in muscle tissue.
 For other drugs, tissue concentrations may not be as high as the
plasma concentration, so it may appear that these drugs distribute
into a relatively small volume.
 It is also important to distinguish among blood, plasma, and
serum.
 Blood refers to the fluid portion in combination with formed
elements (white cells, red cells, and platelets).
 Plasma refers only to the fluid portion of blood (including soluble
proteins but not formed elements).
 When the soluble protein fibrinogen is removed from plasma, the
remaining product is serum .
 These differences in biologic fluids must be recognized when
considering reported drug concentrations.
 The plasma concentration of a drug may be much less than the
whole blood concentration if the drug is preferentially sequestered
by red blood cells.
 CHAPTER-8

DRUG METABOLISM (3 hrs)

 The liver is both a synthesizing and an excreting organ.
 The basic unit of liver is the liver lobule, which contains parenchymal
cells, a network of interconnected lymph and blood vessels.
 The liver consists of large right and left lobes that merge in the
middle.
 The liver is perfused by blood from the hepatic artery; in addition,
the large hepatic portal vein that collects blood from various
segments of the GI tract also perfuses the liver.
 The hepatic artery carries oxygen to the liver and accounts for about
25% of the liver blood supply.
 The hepatic portal vein carries nutrients to the liver and accounts for
about 75% of liver blood flow.
 Blood leaves the liver via the hepatic vein, which empties into the
vena cava.
 The liver also secretes bile acids within the liver lobes, which flow
through a network of channels and eventually empty into the
common bile duct.
 The common bile duct drains bile and biliary excretion products from
both lobes into the gallbladder.
 The liver is the major organ responsible for drug metabolism.
However, intestinal tissues, lung, kidney, and skin also contain
appreciable amounts of biotransformation enzymes
 Drug metabolism in the liver has been shown to be flow and site
dependent.
 Some enzymes are reached only when blood flow travels from a
given direction.
 The quantity of enzyme involved in metabolizing drug is not
uniform throughout the liver.
 Consequently, changes in blood flow can greatly affect the fraction
of drug metabolized.
 Clinically, hepatic diseases, such as cirrhosis, can cause tissue
fibrosis, necrosis, and hepatic shunt, resulting in changing blood
flow and changing bioavailability of drugs.
 For this reason, and in part because of genetic differences in
enzyme levels among different subjects and environmental
factors, the half-lives of drugs eliminated by drug metabolism
are generally very variable.
 A pharmacokinetic model simulating hepatic metabolism should
involve several elements, including the heterogenicity of the
liver, the hydrodynamics of hepatic blood flow, the nonlinear
kinetics of drug metabolism, and any unusual or pathologic
condition of the subject.
 Most models in practical use are simple or incomplete models,
however, because insufficient information is available about an
individual patient.
 For example, the average hepatic blood flow is usually cited as
1.3–1.5 L/min.
 Actually, hepatic arterial blood flow and hepatic venous (portal)
blood enter the liver at different flow rates, and their drug
concentrations are different.
 It is possible that a toxic metabolite may be transiently higher
in some liver tissues and not in others.
 The pharmacokinetic challenge is to build models that predict
regional (organ) changes from easily accessible data, such as
plasma drug concentration.
Phase I Reactions
• Usually, phase I biotransformation reactions occur first and
introduce or expose a functional group on the drug molecules.
• For example, oxygen is introduced into the phenyl group on
phenylbutazone by aromatic hydroxylation to form
oxyphenbutazone, a more polar metabolite.
• Codeine is demethylated to form morphine.
Conjugation (Phase II) Reactions
• Once a polar constituent is revealed or placed into the molecule, a
phase II or conjugation reaction may occur. Common examples
include the conjugation of salicyclic acid with glycine to form
salicyluric acid or glucuronic acid to form salicylglucuronide.
• Conjugation reactions use conjugating reagents, which are derived
from biochemical compounds involved in carbohydrate, fat, and
protein metabolism.
• These reactions may include an active, high-energy form of the
conjugating agent, such as uridine diphosphoglucuronic acid
(UDPGA), acetyl CoA…
 The process of biotransformation or metabolism is the
enzymatic conversion of a drug to a metabolite.
 In the body, the metabolic enzyme concentration is constant
at a given site, and the drug (substrate) concentration may
vary.
 When the drug concentration is low relative to the enzyme
concentration, there are abundant enzymes to catalyze the
reaction, and the rate of metabolism is a first-order process.
 Saturation of the enzyme occurs when the drug concentration
is high, all the enzyme molecules become complexed with
drug, and the reaction rate is at a maximum rate; the rate
process then becomes a zero-order process .
 The maximum reaction rate is known as V max, and the
drug concentration at which the reaction occurs at half the
maximum rate corresponds to a composite parameter K M.
 These two parameters determine the profile of enzyme
reaction rate at various drug concentrations.
 The relationship of these parameters is described by the
Michaelis–Menten equation.
 Enzyme kinetics generally considers that 1 mole of drug
interacts with 1 mole of enzyme to form an enzyme–drug (ie,
enzyme–substrate) intermediate.
 The enzyme-drug intermediate further reacts to yield a
reaction product or a drug metabolite .
 The rate process for drug metabolism is described by the
Michaelis–Menten equation, which assumes that the rate of an
enzymatic reaction is dependent on the concentrations of both
the enzyme and the drug and that an energetically favored
drug–enzyme intermediate is initially formed, followed by the
formation of the product and regeneration of the enzyme.

Fig: Michaelis–Menten enzyme kinetics.

The hyperbolic relationship between enzymatic reaction velocity
and the drug substrate concentration is described by
Michaelis–Menten enzyme kinetics.
 The K M is the substrate concentration when the velocity of the
reaction is at 0.5V max.
 The velocity or rate (v) of the reaction is the rate for the formation
of the product (metabolite), which is also the forward rate of
decomposition of the ED intermediate.
 Therefore, the velocity of metabolism is given by the equation:
where describes the
rate of metabolite formation, or the Michaelis–Menten equation.
 The maximum velocity (V max) corresponds to the rate when all of
the available enzyme is in the form of the drug-enzyme ( ED)
intermediate.
 At V max, the drug (substrate) concentration is in excess, and the
forward reaction, k 3[ED], is dependent on the availability of more
free enzyme molecules.
 The Michaelis-constant,K M, is defined as the substrate
concentration when the velocity (v) of the reaction is equal to one-
half the maximum velocity, or 0.5V max.
 The K M is a useful parameter that reveals the concentration of the
substrate at which the reaction occurs at half V max.
 In general, for a drug with a large K M, a higher
concentration will be necessary before saturation is reached.
 The Michaelis–Menten equation assumes that one drug
molecule is catalyzed sequentially by one enzyme at a time.
 However, enzymes may catalyze more than one drug
molecule (multiple sites) at a time, which may be
demonstrated in vitro.
 In the body, drug may be eliminated by enzymatic reactions
(metabolism) to one or more metabolites and by the
excretion of the unchanged drug via the kidney.
 In the Michaelis–Menton equation is used for modeling drug
conversion in the body.
 The relationship of the rate of metabolism to the drug concentration
is a nonlinear, hyperbolic curve.
 To estimate the parameters V max and K M, the reciprocal of the
Michaelis–Menten equation is used to obtain a linear relationship.

is known as the Lineweaver–Burk

equation, in which K M and V max may be estimated from a plot of 1/v
versus 1/[D].
 Although the Lineweaver–Burk equation is widely used, other
rearrangements of the Michaelis–Menten equation have been used
to obtain more accurate estimates of V max and K M.
 In drug, concentration [D] is replaced by C, which represents drug
concentration in the body.
Kinetics of Enzyme Inhibition
 Many compounds (eg, cimetidine) may inhibit the enzymes that
metabolize other drugs in the body.
 An inhibitor may decrease the rate of drug metabolism by
several different mechanisms.
 The inhibitor may combine with a cofactor such as NADPH2
needed for enzyme activity, interact with the drug or substrate,
or interact directly with the enzyme.
 Enzyme inhibition may be reversible or irreversible.
 The type of enzyme inhibition is usually classified by enzyme
kinetic studies and observing changes in the K M and V max ().
 In the case of competitive enzyme inhibition, the inhibitor and
drug–substrate compete for the same active center on the
enzyme.
 The drug and the inhibitor may have similar chemical
structures.
 An increase in the drug (substrate) concentration may
displace the inhibitor from the enzyme and partially or fully
reverse the inhibition.
 Competitive enzyme inhibition is usually observed by a
change in the K M, but the V max remains the same.
 The equation for competitive inhibition is

where [I] is the inhibitor concentration and k i is the inhibition

constant, which is determined experimentally.
 In noncompetitive enzyme inhibition, the inhibitor may inhibit
the enzyme by combining at a site on the enzyme that is
different from the active site (ie, an allostericsite).
 In this case, enzyme inhibition depends only on the inhibitor
concentration.
 In noncompetitive enzyme inhibition, K M is not altered, but V
max is lower.

 Noncompetitive enzyme inhibition cannot be reversed by

increasing the drug concentration, because the inhibitor will
interact strongly with the enzyme and will not be displaced by
the drug.
 For a noncompetitive reaction,

 The one-compartment model may be used to estimate

simultaneously both metabolite formation and drug decline in
the plasma.
 For example, a drug is given by intravenous bolus injection and
the drug is metabolized by more than one parallel pathway.
 Assume that both metabolites and parent drug concentrations
follow linear (first-order) pharmacokinetics at therapeutic
concentrations.
 The elimination rate constant and the volume of distribution for
each metabolite and the parent drug are obtained from curve
fitting of the plasma drug concentration–time and each
metabolite concentration–time curves.
 If the metabolites are available, each metabolite should be
administered IV separately, to verify the pharmacokinetic
parameters independently.
 The rate of elimination of the metabolite may be faster or
slower than the rate of formation of the metabolite from the
drug.
 Generally, metabolites such as glucuronide, sulfate, or
glycine conjugates are more polar or more water soluble
than the parent drug and will be eliminated more rapidly
than the parent drug.
 Therefore, the rate of elimination of each of these
metabolites is more rapid than the rate of formation.
 In contrast, if the drug is acetylated or metabolized to a less
polar or less water-soluble metabolite, then the rate of
 In this case, metabolite accumulation will occur.
 Compartment modeling of drug and metabolites is relatively
simple and practical.
 The major shortcoming of compartment modeling is the lack of
realistic physiologic information when compared to more
sophisticated models that take into account spatial location of
enzymes and flow dynamics.
 However, compartment models are useful for predicting drug
and metabolite plasma levels.
Liver Extraction Ratio
 Because there are many other reasons for a drug to have a
reduced F value, the extent of first-pass effects is not very
precisely measured from the F value.
 The liver extraction ratio (ER) provides a direct measurement of
drug removal from the liver after oral administration of a drug.

 where C a is the drug concentration in the blood entering the liver

and C v is the drug concentration leaving the liver.

 Because C a is usually greater than C v, ER is usually less than 1.

 For example, for propranolol, ER or [ E] is about 0.7-that is, about

70% of the drug is actually removed by the liver before it is
available for general distribution to the body.
 By contrast, if the drug is injected intravenously, most of the drug
would be distributed before reaching the liver, and less of the
drug would be metabolized.
 CHAPTER-9

DRUG EXCRETION
 Drugs are removed from the body by various elimination
processes.
 Drug elimination refers to the irreversible removal of drug from the
body by all routes of elimination.
 Drug elimination is usually divided into two major components:
excretion and biotransformation.
 Drug excretion is the removal of the intact drug.
 Nonvolatile drugs are excreted mainly by renal excretion, a process
in which the drug passes through the kidney to the bladder and
ultimately into the urine.
 Other pathways for drug excretion may include the excretion of
drug into bile, sweat, saliva, milk (via lactation), or other body
fluids.
 Volatile drugs, such as gaseous anesthetics or drugs with high
volatility, are excreted via the lungs into expired air.
 Biotransformation or drug metabolism is the process by which the
drug is chemically converted in the body to a metabolite.
 Biotransformation is usually an enzymatic process.
 A few drugs may also be changed chemically by a nonenzymatic
process (eg, ester hydrolysis).
 The enzymes involved in the biotransformation of drugs are
located mainly in the liver.
 Other tissues such as kidney, lung, small intestine, and skin also
contain biotransformation catalyzing enzymes.
 Drug elimination in the body involves many complex rate
processes.
 Although organ systems have specific functions, the tissues within
the organs are not structurally homogeneous, and elimination
processes may vary in each organ.
 Elimination is overall first-order elimination rate process.
 The term clearance describes the process of drug elimination from
the body or from a single organ without identifying the individual
processes involved.
 Clearance may be defined as the volume of fluid cleared off drug
from the body per unit of time.
 The units for clearance are milliliters per minute (mL/min) or liters
per hour (L/hr).
 The volume concept is simple and convenient, because all drugs are
dissolved and distributed in the fluids of the body.
 The advantage of the clearance approach is that clearance applies to
all elimination rate processes, regardless of the mechanism for
elimination.
 In addition, for first–order elimination processes, clearance is a
constant, whereas drug elimination rate is not constant.
 For example, clearance considers that a certain portion or percent of
the distribution volume is cleared of drug over a given time period.
 Clearance is a measure of the removal of drug from the body.
 Plasma drug concentrations are affected by the rate at which drug
is administered, the volume in which it distributes, and its
clearance.
 A drug's clearance and the volume of distribution determine its
half-life.
 Clearance (expressed as volume/time) describes the removal of
drug from a volume of plasma in a given unit of time (drug loss
from the body).
 Clearance does not indicate the amount of drug being removed.
 It indicates the volume of plasma (or blood) from which the drug is
completely removed, or cleared, in a given time period.
 Total body clearance of a drug is the sum of all the clearances by
various mechanisms
 Where, Clt = total body clearance (from all mechanisms, where t
refers to total); Clr = renal clearance (through renal excretion); Clm
= clearance by liver metabolism or biotransformation; Clb = biliary
clearance (through biliary excretion); and Clother = clearance by all
other routes (gastrointestinal tract, pulmonary, etc.).
 For an agent removed primarily by the kidneys, renal clearance
(Clr) makes up most of the total body clearance.
 For a drug primarily metabolized by the liver, hepatic clearance
(Clm) is most important.
 A good way to understand clearance is to consider a single well-
perfused organ that eliminates drug.
 Blood flow through the organ is referred to as Q (mL/minute),
where Cin is the drug concentration in the blood entering the organ
and Cout is the drug concentration in the exiting blood.
 If the organ eliminates some of the drug, Cin is greater than Cout.
 We can measure an organ's ability to remove a drug by relating Cin
and Cout.
 This extraction ratio (E) is:
 This ratio must be a fraction between zero and one. Organs that are
very efficient at eliminating a drug will have an extraction ratio
approaching one (i.e., 100% extraction).
 The drug clearance of any organ is determined by blood flow and the
extraction ratio: organ clearance = blood flow × extraction ratio
 or:

 If an organ is very efficient in removing drug (i.e., extraction ratio

near one) but blood flow is low, clearance will also be low.
 Also, if an organ is inefficient in removing drug (i.e., extraction ratio
close to zero) even if blood flow is high, clearance would again be
low.
 Clearance can also be a useful parameter for constructing dosage
recommendations in clinical situations.
 It is an index of the capacity for drug removal by the body organs.

 Clearance can be related to drug dose by first evaluating the

plasma drug concentration versus time curve after a dose.
 The AUC is determined by drug clearance and the dose given:

,where: X0 = drug dose, and Total body clearance (Clt) is the most
important pharmacokinetic parameter because it relates the
dosing rate of a drug to its steady-state concentration.
It is usually used to calculate a maintenance dosing regimen.
 An estimate of Clt for a drug is usually obtained after a single
intravenous bolus dose
 After steady state has been achieved with IV dosing

 The dose given (X0), the dosing interval (τ) and average
concentration of drug in the plasma at steady state ( ).
 Chapter-10

Pharmacokinetics models: Compartment models, Non-

compartment models (4 hrs)
 The handling of a drug by the body can be very complex, as several
processes (such as absorption, distribution, metabolism, and
elimination) work to alter drug concentrations in tissues and fluids.
 Simplifications of body processes are necessary to predict a drug's
behavior in the body.
 One way to make these simplifications is to apply mathematical
principles to the various processes.
 To apply mathematical principles, a model of the body must be
selected.
 A basic type of model used in pharmacokinetics is the
compartmental model.
 Compartmental models are categorized by the number of
compartments needed to describe the drug's behavior in the body.
 There are one compartment, two-compartment, and
multicompartment models.
 The compartments do not represent a specific tissue or fluid but
may represent a group of similar tissues or fluids.
 These models can be used to predict the time course of drug
concentrations in the body
 Compartmental models are termed deterministic because the
observed drug concentrations determine the type of
compartmental model required to describe the pharmacokinetics
of the drug.
 To construct a compartmental model as a representation of the
body, simplifications of body structures are made.
 Organs and tissues in which drug distribution is similar are grouped
into one compartment.
 For example, distribution into adipose tissue differs from
distribution into renal tissue for most drugs.
 Therefore, these tissues may be in different compartments.

 The highly perfused organs (e.g., heart, liver, and kidneys) often
have similar drug distribution patterns, so these areas may be
considered as one compartment.
 The compartment that includes blood (plasma), heart, lungs, liver,
and kidneys is usually referred to as the central compartment or
the highly blood-perfused compartment.
 The other compartment that includes the fat tissue, muscle tissue,
and cerebrospinal fluid is the peripheral compartment, which is
less well perfused than the central compartment.
 The value of any model is determined by how well it predicts drug
concentrations in fluids and tissues.
 Generally, it is best to use the simplest model that accurately predicts
changes in drug concentrations over time.
 If a one-compartment model is sufficient to predict plasma drug
concentrations (and those concentrations are of most interest to us),
then a more complex (two compartment or more) model is not needed.
 However, more complex models are often required to predict tissue
drug concentrations.
 Drugs extensively distributed in tissue (such as lipophilic drugs like the
benzodiazepines) or those that have extensive intracellular uptake may
be better described by the more complex models.
 The one-compartment model is the most frequently used model in
clinical practice.
 In structuring the model, a visual representation is helpful.
 The compartment is represented by an enclosed square or
rectangle, and rates of drug transfer are represented by straight
arrows.
 The arrow pointing into the box simply indicates that drug is put
into that compartment.
 And the arrow pointing out of the box indicates that drug is leaving
the compartment.
 This model is the simplest because there is only one compartment.
 All body tissues and fluids are considered a part of this
compartment.
 Furthermore, it is assumed that after a dose of drug is
administered, it distributes instantaneously to all body areas.
1. One compartment model
All drugs initially distribute into a central compartment (Vc) before
distributing into the peripheral compartment (Vt).
• If a drug rapidly equilibrates with the tissue compartment, then,
for practical purposes, we can use the much simpler one-
compartment model which uses only one volume term, the
apparent volume of distribution, Vd.

• Example
The distribution phase for aminoglycosides is only 15-30 minutes,
therefore, we can use a one-compartment model with a high
degree of accuracy.
• Serum level plot for a 1-compartment model
• Yields a straight line when using a log scale on the y-axis.

• Two compartment model

Drugs which exhibit a slow equilibration with peripheral tissues, are
best described with a two compartment model.
• Example: Vancomycin is the classic example, it's distribution phase is
1 to 2 hours.
• Therefore, the serum level time curve of vancomycin may be more
accurately represented by a 2-compartment model.
• Serum level plot for a 2-compartment model
• Yields a biphasic line when using a log scale on the y-axis.
 Chapter-11

Non-linear pharmacokinetics (1 hr)

 In linear pharmacokinetics, the rate of elimination is proportional to the
drug concentration.
 This means that the higher the drug concentration, the higher its
elimination rate. In other words, the elimination processes are not
saturated and can adapt to the needs of the body, to reduce
accumulation of the drug.
 Plasma concentration and AUC is linear with drug dose in first-order
processes, this concept is referred to as linear pharmacokinetics.
 For example, if a 100-mg daily dose of a drug produces a steady-state
peak plasma concentration of 10 mg/L, we know that a 200-mg daily
dose will result in a steady-state plasma concentration of 20 mg/L.
 With some drugs (e.g., phenytoin and aspirin), however, the r/nships of
drug dose to plasma concentrations and AUC are not linear.
 As the drug dose increases, the peak concentration and the resulting AUC
do not increase proportionally.
 Therefore, such drugs are said to follow nonlinear, zero-order, or dose-
dependent pharmacokinetics (i.e., the pharmacokinetics change with the
dose given).
 Non-linear pharmacokinetics is a Kinetics resulting from saturable
drug transfer, leading to variation of the standard kinetic
parameters with drug concentration
 It is usually due to saturation occuring in one of the
pharmacokinetic mechanisms: protein binding, hepatic
metabolism, or active renal transport of the drug.
 Saturable elimination: above a certain drug concentration, the
elimination rate tends to reach a maximal value.
 Once this maximum capacity is reached, there is no further
increase in the elimination rate when plasma drug concentration
increases.
 Therefore, in nonlinear elimination kinetics, the drug clearance
decreases with increasing drug concentration.
 Just as with drugs following linear pharmacokinetics, it is important
to predict the plasma drug concentrations resulting from a drug
dose.
 Saturable binding or reabsorption: above a certain drug
concentration, drug protein binding or drug reabsorption in kidney
tubules tends to reach maximal capacity.
 This leads to a disproportionate increase in the rate of elimination
with increasing drug concentrations (e.g. with high doses of
vitamin).
 95% of the drugs in use at therapeutic concentrations are
eliminated by first order elimination kinetics.
 A few substances are eliminated by zero-order elimination kinetics,
because their elimination process is saturated.
 Examples are Ethanol, Phenytoin, Salicylates, Cisplatin, Fluoxetin,
Omeprazol.
 Because in a saturated process the elimination rate is no longer
proportional to the drug concentration but decreasing at higher
concentrations, zero-order kinetics are also called “non-linear
kinetics”
 Saturable absorption: above a certain drug concentration at the
absorption site, there is no further increase in the absorption rate.
 Therefore, absorption rate constant and possibly bioavailability
decrease with doses leading to concentrations at the absorption site
above the maximal absorption capacity.
 Even though absorption and distribution can be nonlinear, the term
nonlinear pharmacokinetics usually refers to the processes of drug
elimination.
 When a drug exhibits nonlinear pharmacokinetics, usually the
processes responsible for drug elimination are saturable at
therapeutic concentrations.
 These elimination processes may include renal tubular secretion (as
seen with penicillins) and hepatic enzyme metabolism.
 When an elimination process is saturated, any increase in drug dose
results in a disproportionate increase in the plasma conc achieved
because the amount of drug that can be eliminated over time cannot
increase.
 This situation is contrary to first-order linear processes, in which an
increase in drug dosage results in an increase in the amount of drug
eliminated over any given period.
 Of course, most elimination processes are capable of being saturated
if enough drug is administered.
 However, for most drugs, the doses administered do not cause the
elimination processes to approach their limitations.
Clinical implications
 For drugs with saturable elimination, an increase in dosage or dosage
frequency can lead to a disproportionate increase in plasma drug
concentration when the rate of elimination tends to reach its
maximum capacity. Therefore, changing dose is difficult and
unpredictable.
 Special caution should be taken when deciding to change the dosage
regimen of such drugs, particularly if elevated plasma concentrations
are associated with toxicity (e.g. Phenytoin).
 On the other hand, for drugs with saturable absorption or tubular
reabsorption, a change in dosage may lead to a less than
proportional change in plasma concentration.
 This is important in evaluating the efficiency of a drug dosage
regimen.
 Saturable elimination (e.g. saturable metabolism of the drug) may
be quantified by the Michaelis-Menten equation :
 Vm = maximum rate
 Km = Michaelis-Menten constant (drug conc. at which the rate of
elimination is 50% of Vm)
 C = Plasma drug concentration
 CHAPTER-12

POPULATION PHARMACOKINETICS
 Population pharmacokinetics is study of the extent, sources and
correlates of variability in drug pharmacokinetics within a patient
population.
 Certain patient characteristics, such as age, body weight, comorbidity
and comedication, can alter the pharmacokinetic parameters of a
drug.
 Population pharmacokinetics seeks to assess the extent of the
variability of these parameters among a patient population and to
identify the factors that are responsible for such variability.
 Population pharmacokinetics includes:
1. Assessment of global variability of the plasma drug concentration
profile in a patient population.
2. Allocation of this variability to pharmacokinetic parameters (e.g.
variability of clearance, bioavailability, etc).
3. Explanation of variability by identifying factors of demographic,
pathophysiological, environmental, or concomitant drug-related
origin that may influence the pharmacokinetic parameters.
4. Quantitative estimation of the magnitude of the unexplained
variability in the patient population.
SOURCES OF PHARMACOKINETIC VARIATION
 An important reason for pharmacokinetic drug monitoring is that a
drug's effect may vary considerably among individuals given the same
dose.
 These differences in drug effect are sometimes related to differences
in pharmacokinetics.
 Some factors that may affect drug pharmacokinetics are discussed
below.
 However, irrespective of pharmacokinetics, drug effects may vary
among individuals because of differences in drug sensitivity.
• Sophisticated pharmacostatistical models are needed to analyze
population pharmacokinetics.
Clinical implications
 Population pharmacokinetics in the drug development process
helps identify differences in drug safety and efficiency among
population subgroups.
 The mean values of pharmacokinetic parameters allow the
elaboration of the standard dosage regimen of the drug.
 Variability that is due to influencal factors leads to dosage
adaptation proposed for patient subsets.
 Unexplained variability reflects the reproducibility of
pharmacokinetics.
 This is important because the efficacy and safety of a drug may
decrease as unexplained variability increases.
Therapeutic applications of pharmacokinetics
1. DOSAGE REGIMEN is Decision of drug administration regarding
formulation, route of administration, drug dose, dosing interval
and treatment duration."
 LD = Loading Dose
 MD = Maintenance
 dint = dosing interval
 The objective of drug therapy is to bring plasma concentration
within the therapeutic window.
 The dosage regimen is the modality of drug administration that is
chosen to reach the therapeutic objective.
 This depends on the drug used, the condition to be treated, and
the patient's characteristics.
 The decisions defining dosage regimen are about:
 Route of administration
 Galenic formulation
 Unit dose
 Frequency
 Loading dose
 Length of treatment
2. DOSAGE INDIVIDUALIZATION Is adaptation of the dosage
regimen in function of the clinical characteristics of the
individual, aiming to achieve the best possible therapeutic
efficiency at the lowest risk of unwanted effects.
 The objective of drug therapy is to produce, the desired
therapeutic effect, with the highest chance and minimum toxic
effects.
 As described, the dosage regimen must be first adapted to the
patient's characteristics and comorbidities.
 This initial adaptation realizes a priori individualization.
 After initiating therapy, the patient's response to the drug must be
evaluated and the dosage regimen further adapted in case of
ineffective therapy or appearance of undesirable effects.
 In selected circumstances, the follow-up of an effect marker may
improve the monitoring of treatment.
 Adaptation in response to such feedback information realizes the a
posteriori individualization.
 The reasons for failure of drug treatment can drive from physiological inter-
individual variation of pharmacokinetic parameters, which cannot always be
evaluated prior to initiation of drug therapy (e.g. genetic metabolic differences).
 Other causes of treatment failure are variation in response due to inter-individual
differences in pharmacodynamics (e.g. sensitivity towards the drug), including
drug tolerance (diminished pharmacologic responsiveness to the drug).
 Disease states can further alter the response to drugs, and draw attention to
dosage individualization.
Clinical implications
 A priori individualization must be considered each time a drug treatment is
introduced.
 After initiating drug therapy, the desired response (e.g. analgesia) and the
appearance of undesirable effects (e.g. sleepiness) should be evaluated for each
patient.
 If these features are not satisfactory, an alteration of the dosage regimen should
be discussed.
 For some drugs, it is standard practice to monitor surrogate markers (e.g.
prothrombin time) for evaluating the effectiveness of therapy.
 For drugs with a narrow therapeutic window having no such effect marker easily
followed, regimens can be personalized using (TDM).
Related terms
• Therapeutic Drug Monitoring (TDM): In TDM, drug plasma or blood
concentration is measured and the regimen is adapted until the plasma
concentration is brought into a predefined therapeutic range.
3. PHARMACOKINETIC VARIABILITY Is inter-individual variations of a drugs
pharmacokinetic parameters, resulting in fairly different plasma
concentration-time profiles after administration of the same dose to
different patients.
• Substantial differences in response to most drugs exist among patients.
• Therefore, the therapeutic standard dose of a drug, which is based on
trails in healthy volunteers and patients, is not suitable for every patient.
• Variability exists in both pharmacokinetics and pharmacodynamics.
• For a typical drug, one standard deviation in the values observed for
bioavailability (F), clearance (CL) and volume of distribution (Vd) would
be about 20%, 50% and 30% respectively.
• Therefore, 95% of the time, the average concentration (Cav) will be
between 35% and 270% of the target value.
 The most important factors in variability of pharmacokinetic
parameters are:
 Genetic
 Disease
 Age and body size
 Concomitant drugs
 Environmental factors (e.g. foods, pollutants)
 Other factors include compliance, pregnancy, alcohol intake,
seasonal variations, gender, or conditions of drug intake.
Clinical implications
 Individualization of dosage regimen to a particular patient is critical
for optimal therapy.
 This is particularly true for drugs with a narrow therapeutic window.
 Until recently, reasonable individual estimates of dosage regimen
were based on the patient's weight, age, renal, hepatic and
cardiovascular function and concomitant drug administration.
 Taking into account genetic markers is now proposed to complete
dosage regimen decisions.
4. PHARMACOGENETICS Is study of hereditary sources of variation in
drug response, their prevalence and mechanism."
 Patients vary widely in their responses to drugs.
 Important factors in variability are drug metabolism and drug
transport.
 Interindividual variation of drug metabolism is due to several factors.
 Genetic polymorphism is one of them and is defined by the presence,
in a normal population, of monogenic traits that exist in at least two
phenotypes, neither of which is rare (less than 1%).
 The clinical implications of genetic polymorphism in drug metabolism
depend on whether activity or toxicity lies with the affected substrate
or the metabolite, as well as the importance of the pathway to
overall elimination.
 If the parent drug is active, there is a greater likelihood of adverse
reactions in poor metabolizers and ineffective therapy in extensive
metabolizer.
 Likewise, if the metabolite is active or toxic, there is a greater
likelihood of adverse reactions in the extensive metabolizers and
ineffective therapy in the poor metabolizers.
 Genetic variability may effect drug clearance but also drug
bioavailability (for drugs with a high hepatic extraction ratio).
5. DISEASE AND VARIABILITY
 Concurrent diseases affecting the patient, including the one for
which the drug is used, can modify drug response.
 Diseases of the organs of elimination, e.g the liver and the kidneys,
are responsible for large variations in drug pharmacokinetics.
 Circulatory disorders are also important in pharmacokinetic
variability.
 Diminished vascular perfusion of one or more parts of the body is
encountered in conditions such as cardiac failure.
 This diminished perfusion can affect the different pharmacokinetic
mechanisms: perfusion of the absorption sites influences absorption,
variation of body perfusion may alter the drug distribution to certain
organs, perfusion of the liver and kidneys affect the metabolism and
excretion of the drug.
 Drugs that are largely metabolized in the liver are affected by liver
diseases such as cirrhosis.
 Biliary excretion may be altered by conditions such as obstructive
jaundice.
 It is worthfull to remind that hepatic disorders affect not only the
metabolism and excretion of drugs but also their absorption (through
first-pass effect) and distribution (through protein binding).
 In conditions such as cirrhosis, oral bioavailability of drugs undergoing
a substantial hepatic first pass effect can be greatly increased.
 In patients with hepatic impairment, there is a decrease in plasma
protein synthesis by the liver.
 This decrease may affect the volume of distribution of drugs that are
extensively bound to these proteins.
 In patients with a compromised renal function, urinary excretion of
drugs is diminished.
 Therefore, the clearance of many drugs is also reduced.
 In first approxiamation, this reduction is proportional to the decrease
in renal function.
 Notice that renal diseases may also affect the pharmacokinetics of
drugs eliminated through metabolism.
 For example, insufficient excretion of metabolites can induce toxicity.
 Also, uremia decreases the liver enzymatic activity and displaces
drugs from plasma proteins.
Clinical implications
 Special attention should be given to the evaluation of the patients
renal and hepatic function, and the dosage regimen of many drugs
should be adapted if an organ impairment is observed.
 During repeated administration, care should be given while adapting
the dosage regimen in patients suffering from conditions that
diminish the clearance of the drug.
 In such conditions, toxic accumulation may occur.
 Also, the half-life of the drug is prolonged and therefore, the time
needed to reach steady state is longer.
Assessment
 For renal failure, creatinine clearance (CLcr) is considered to be a
suitable marker of renal function and is used for dosage adaptation.
 There is no widely accepted marker to quantify the hepatic function.
6. AGE Is variability of pharmacokinetic parameters due to age.
Aging is an additional source of variability in drug pharmacokinetics.
This age-induced variability is considered for each of the four main
pharmacokinetic mechanisms:
a) Absorption: Drug absorption does not appear to change dramatically
with age.
 Generally, changes in the rate rather than in the extent of absorption
are found. As exceptions, marked differences in absorption are
observed in the neonatal period and in the elderly.
 In both cases, a decrease in hepatic metabolism and first pass effect
may lead to an increase in oral bioavailability of some drugs.
b) Distribution: The volume of distribution is frequently directly
proportional to body weight and modulated by age.
 In some cases, age-related changes in drug binding can affect the
volume of distribution (e.g. decrease in extracellular fluid in the
elderly).
c) Metabolism: Aging clearly affects metabolism.
 The enzymes involved in both phase I and phase II metabolism
mature gradually following the first two to four weeks following
postpartum.
 Full maturity appears in the second decade of life with a subsequent
slow decline in function associated with aging.
 The overall decrease of metabolic clearance is around 1 % per year.
d) Excretion : Renal clearance normalized for bodyweight is depressed
in neonates but then rapidly increases to reach a maximum at six
months.
 Throughout adulthood, age is associated with an average decrease
in renal function of 1% per year.
 But most strikingly, age is associated to an increase in the variability
of renal clearance among individuals.
Clinical implications
 Adaptation of drug regimens is most important for neonates, infants
and in the elderly.
 The lack of maturation of renal and hepatic function in the neonates
and young infants necessitates that the rate of administration of
drugs be reduced.
 In children, drug clearance is considered to correlate better with
body surface area than body weight.
 Therefore, higher maintenance dose per kilogram body weight are
required the smaller and the younger the child.
7. CONCOMITANT DRUGS
 In many patients, several drugs are given concomitantly in order
to increase the treatment efficiency or to treat diseases occurring
simultaneously.
 In such cases, pharmacokinetic interactions between drugs may
occur and the therapeutic efficacy or the toxicity of the drugs
implied may be affected.
 Drug interactions may occur during absorption: a drug can
influence the rate or the extent of absorption of another drug.
 For example, metoclopramide hastens gastric emptying therefore
accelerating the rate of absorption of certain drugs, e.g.
paracetamol.
 Calcium forms insoluble complexes in the intestinal lumen with
tetracycline, therefore decreasing its bioavailability.
 Erythromycin can dramatically increase the oral bioavailability of
midazolam by inhibiting its hepatic first-pass effect. 
 Distribution may also be influenced by drug interactions.
 Most commonly, a drug that is highly bound to plasma or tissue
proteins may be displaced from its binding sites by another drug.
 In an acute situation, this interaction may be significant if the
concentration of the displacer is sufficiently high to occupy most of
the protein binding sites.
 The sites available to bind the displaced drug are thus lowered and
the amount of unbound drug, the pharmacologically active moiety, is
increased.
 When the drug and the displacer are given chronically, the unbound
concentration of the drug depends on its extraction ratio.
 For drugs with a low extraction ratio, there is an overall decrease in
the total plasma concentration but no change in the unbound
concentration.
 On the other hand, for drugs with a high extraction ratio, the total
plasma concentration is unchanged but the unbound drug
concentration is increased and this may lead to toxicity.
 Most importantly, elimination may be affected by drug
interactions.
 A drug may inhibit the renal excretion of another drug by
competing with its renal tubular transport.
 Also, drug metabolism may be strongly induced or inhibited by the
administration of a concomitant drug.
 The clearance of the drug is thus modified.
 Therefore, this type of interaction may easily lead to toxicity or
ineffective therapy.
 Both induction and inhibition can mimic pharmacogenetic
influences by phenocopying.
Clinical implications
 A drug interaction is likely to be detected when the interacting
drug is initiated or withdrawn.
 It is to be noted that for affected drugs with very long half-lives,
changes in response are insidious and may not be associated with the
interaction with the causative drug, which was either initiated or
stopped sometime previously.
 The half-life of the drug may be prolonged and therefore, in repeated
administration, the time required to reach steady state and to
undergo the effects of changes in plasma concentration such as
toxicity are increased.
 At the other extreme, drug use in the elderly generally requires
significant reductions in drug dose reflecting the general decline in
body fxn with age.
 So, increase attention should be given to both Rx failure and toxicity.
 In the elderly, there should be awareness of possible exaggerated
pharmacodynamic responses, as there may be a increase in sensitivity
of target organs.
Reading Assignment
Pharmacokinetics of particular drugs
 Aspirin
 Digoxin
 Furosemide
 Morphine
 Nitroglycerin
 Paracetamol
 Phenytoin
 Rifampicin
 Theophylline
 Thiopental and vancomycin
THE COURSE IS ENDED!