ADME

PHARMACOKINETICS
What the body does to drug
• ABSORPTION

• DISTRIBUTION

• METABOLISM

• EXCRETION
 Pharmacokinetics
The characteristics of a drug (onset of action,
intensity of effect & duration of action) are
controlled by four fundamental pathways.
1. Drug absorption from the site of
administration that allows the agent access
to the plasma
2. Distribution from the plasma into the
interstitial tissue and intracellular fluids;
presented to the cells
3. Metabolism occurs in the liver, kidneys or
other tissues; this may alter the drugs
function.
4. Elimination occurs through the urine, bile,
feces or expired air, this often involves
some chemical change to the drug.
 Routes Of Administration

Routes Of Drug
Administration

Parenteral Enteral

Injection Topical Respiratory Rectal Oral

Routes of Administration
 Absorption

The movement of a drug from its

point of entry into the body into
systemic circulation
 Main factors affecting oral
absorption

• Physiological factors
• Physical-chemical factors
• Formulation factors
Physiological factors affecting oral
absorption
• Membrane physiology
• Passage of drugs across membranes
• Active transport
• Facilitated diffusion
• Passive diffusion
• Pinocytosis
• Pore transport
• Ion pair formation
• Gastrointestinal physiology
• Characteristics of GIT physiology and
drug absorption
• Gastric emptying time and motility
• Effect of food on drug absorption
• Double peak phenomena
• Malabsorption
 A. Membrane physiology
• Membrane structure
1900 Overton

Biologic membrane is mainly lipid in nature but contains small aqueous

channels or pores.
 The Davson-Danielli Model
.

• Suggested that there is also a layer of

protein on the membrane
 Modified Davson-Danielli Model

• Later work (Danielli, 1975) suggested the

presence of "active patches" and protein
lining to pores in the membrane.
 The Fluid Mosaic Model
Lipid bilayer is retained but the protein drifts between
the lipid rather than forming another layer on either
side of the lipid bilayer.
 Loosely Attached Cell Barrier

Cell Barrier with Tight Junctions

Examples:

Blood-brain barrier
Renal tubules
Blood capillaries and renal glomerular membranes:
Hepatic blood vessels
Renal glomerular Membrane
and Blood-brain barrier
B. Passage of drugs across membranes
• Active transport or carrier mediated
transport:

Carrier-Mediated Transport Process

Active transport
• Active transport requires a carrier
molecule and a form of energy.
• The process can be saturated (there are a
finite number of carriers)
• Transport can proceed against a
concentration gradient
• Competitive inhibition is possible
 2.Facilitated diffusion

• A drug carrier is required but no energy

is necessary. e.g. vitamin B12 transport.
• Saturable if not enough carrier
• No transport against a concentration
gradient only downhill but faster
 3.Passive diffusion:

• Most (many) drugs cross biologic membranes by

passive diffusion.

• Diffusion occurs when the drug concentration on

one side of the membrane is higher than that on
the other side. Drug diffuses across the
membrane in an attempt to equalize the drug
concentration on both sides of the membrane.
Diagram of Passive Transport with a
Concentration Gradient
 The rate of transport of drug across the
membrane can be described by
Fick's first law of diffusion

D: diffusion coefficient.
A: surface area.
x: membrane thickness.
(Ch -Cl): concentration difference.
Illustration of Different Transport
Mechanisms
 4.Pinocytosis = Phagocytosis=
Vesicular transport
• Larger particles are not able to move through
membranes or interstitial spaces so other processes must
be available.
• These processes involve the entrapment of larger
particles by the cell membrane and incorporation into
the cell, cytosis.
• A spontaneous incorporation of a small amount of
extracellular fluid with solutes is called pinocytosis.
• Phagocytosis is a similar process involving the
incorporation of larger particles.
• Examples include Vitamin A, D, E, and K, peptides in
newborn.
Endocytosis
 5.Pore transport
• Small drug molecules move through this channel by
diffusion more `rapidly than at other parts of the
membrane. A certain type of protein called transport
protein may form an open channel across the lipid
membrane of cell.

• Very small molecules (such as water, urea and sugar)

are able to rapidly cross cell membrane as if the
membrane contained pores or channels

• This model of transportation is used to explain renal

excretion of drugs and uptake of drugs into the liver.
Pore transport
Ion-pair transport
 6.Ion pair formation

• Strong electrolyte drugs are highly ionized (such as

quaternary nitrogen compounds) with extreme pKa
values, and maintain their charge at physiological pH.
• These drugs penetrate membranes poorly.
• When linked up with an oppositely charged ion, an ion
pair is formed in which the overall charge of the pair is
neutral.
• The neutral complex diffuses more easily across the
membrane.
• An example of this in case of propranolol, a basic drugs
that forms an ion pair with oleic acid.
 C. Gastrointestinal (GI) Physiology
Organs pH Membrane Blood Surface Transit By-
Supply Area Time pass
liver

Buccal approx thin Good, fast small Short yes

6 absorption unless
with low dose controll
ed

Esophagus 6-7 Very - small short, -

thick typically
a few
no seconds,
absorption except
for some
coated
tablets
Stomach 1.7-4.5 normal good small 30 min (liquid) - 120 no
decompos min (solid food),
ition, delayed stomach
weak acid emptying can reduce
unionized intestinal absorption
Duodenu 5-7 normal good very very short (6" long), no
m bile duct, large window effect
surfactan
t
properties

Small 6 -7 normal good very about 3 hours no

Intestine large 10
- 14 ft,
80 cm
2 /cm
Large 6.8 - 7 - good not very long, up to 24 hr lower
Intestine large 4 - colon,
5 ft rectum
yes
 1.Gastric emptying and motility
• Generally drugs are better absorbed in the small intestine
(because of the larger surface area) than in the stomach,
therefore quicker stomach emptying will increase drug
absorption.
• For example, a good correlation has been found between
stomach emptying time and peak plasma concentration for
acetaminophen.
• The quicker the stomach emptying (shorter stomach
emptying time) the higher the plasma concentration. Also
slower stomach emptying can cause increased degradation
of drugs in the stomach's lower pH; e.g. L-dopa.
Dependence of peak acetaminophen plasma
concentration as a function of stomach
emptying half-life
 Factors Affecting Gastric Emptying

• Volume of Ingested Material

• As volume increases initially an increase then a
decrease. Bulky material tends to empty more
slowly than liquids
• Type of Meal
• Fatty food Decrease
• Carbohydrate Decrease
• Temperature of FoodI
• increase in temperature, increase in emptying rate
• Body Position
• Lying on the left side decreases emptying rate.
Standing versus lying (delayed)
• Drugs
• Anticholinergics (e.g. atropine), Narcotic (e.g.
morphine, alfentanil), Analgesic (e.g.
aspirin)Decrease
• Metoclopramide, Domperidone, Erythromycin,
Bethanchol Increase
 3.Effect of Food
• Food can effect the rate of gastric emptying.
• For example fatty food can slow gastric emptying and
retard drug absorption.
• Generally the extent of absorption is not greatly
reduced. Occasionally absorption may be improved ,
• For example, Griseofulvin absorption is improved by
the presence of fatty food. Apparently the poorly
soluble griseofulvin is dissolved in the fat and then
more readily absorbed.
• Propranolol plasma concentrations are larger after
food than in fasted subjects. This may be an interaction
with components of the food.
Effect of Fasting versus Fed on Propranolol
Concentrations
 4.Double peak phenomena
• Some drugs such as cimetidine and rantidine,
after oral administration produce a blood
concentration curve consisting of two peaks.

• The presence of duple peaks has been

attributed to variability in stomach emptying,
variable intestinal motility, presence of food,
enterohepatic cycle or failure of a tablet dosage
form.
 5.Malabsorption
• Malabsorption is any disorder with impaired
absorption of fat, carbohydrate, proteins and
vitamins.

• Drug induced malabsorption has been observed

after administration of neomycine, phenytoine
and anticancer agents.
 Physical-Chemical Factors Affecting
Oral Absorption
• Outline of Physical-chemical factors affecting
oral absorption:
– pH-partition theory
– Lipid solubility of drugs
– Dissolution and pH
– Salts
– Crystal form
– Drug stability and hydrolysis in GIT
– Complexation
– Adsorption
 1.pH-partition theory
• For a drug to cross a membrane barrier it must
normally be soluble in the lipid material of the
membrane to get into membrane and it has to be
soluble in the aqueous phase as well to get out of the
membrane.
• Many drugs have polar and non-polar characteristics
or are weak acids or bases.
• For drugs which are weak acids or bases the pKa of
the drug, the pH of the GI tract fluid and the pH of
the blood stream will control the solubility of the
drug and thereby the rate of absorption through the
membranes lining the GI tract.
 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.
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.
 pH and ionization

Acidic drugs are best absorbed in Acidic

medium

Basic drugs are best absorbed in Basic

medium
PH of the medium

stomach (pH 1~3)

in favour of weak acid
absorption

duodenum (pH 5~7)

in favour of weak base
absorption

ileum (pH 7~8)

in favour of weak base
absorption
 B. Lipid solubility of drugs
• Some drugs are poorly absorbed after oral
administration even though they are non-ionized
in 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 ,
• [ L]conc is the concentration of the drug in lipid
phase,
• [W]conc is the concentration of the drug in
aqueous phase.
• The higher p value, the more absorption is
observed.
• Prodrug is one of the option that can be used to
enhance p value and absorption as sequence.
C. Drug Dissolution
 C. Drug Dissolution
Drug solubilization – breaking drugs into smaller, more Absorbable particles
.
DISINTEGRATION (solid )

DISSOLUTION (solution)

ABSORPTION

SYSTEMIC CIRCULATION (% bioavailability)

56
 D. Salt form

Plot of Dissolved Drug Concentration versus Time

• Salts of weak acids and weak bases generally have
much higher aqueous solubility than the free acid
or base,
• Therefore if the drug can be given as a salt the
solubility can be increased and we should have
improved dissolution.
• One example is Penicillin V.
 E. Crystal form
• Some drugs exist in a number of crystal forms or
polymorphs. These different forms may well have
different solubility properties and thus different
dissolution characteristics.

• Chloramphenicol palmitate is one example which

exists in at least two polymorphs. The B form is
apparently more bioavailable.
Plot of Cp versus Time for Three Formulations of
Chloramphenicol Palmitate
 F. Drug stability and hydrolysis in
GIT
• Acid and enzymatic hydrolysis of drugs in GIT is one of the
reasons for poor bioavailability.

• Penicillin G (half life of degradation = 1 min at pH= 1)

• Rapid dissolution leads to poor bioavailability (due to release

large portion of the drug in the stomach, pH = 1.2)

• Prodrug ( conversion in the GIT to parent compound is rate

limiting step in bioavailability, either positively or negatively)
 G. Complexation
• Complexation of a drug in the GIT fluids may alter rate and extent of
drug absorption.

• Intestinal mucosa + Streptomycin = poorly absorbed complex

• Calcium + Tetracycline = poorly absorbed complex (Food-drug

interaction)

• Carboxyl methylcellulose (CMC) + Amphetamine = poorly absorbed

complex (tablet additive – drug interaction)

– Polar drugs + complexing agent = well-absorbed lipid soluble

complex ( dialkylamides + prednisone)

– Lipid soluble drug + water soluble complexing agent = well-

absorbed water soluble complex ( cyclodextrine)
 H. Adsorption
• Certain insoluble substance may adsorbed co-
administrated drugs leading to poor absorption.
• Charcoal (antidote in drug intoxication).
• Cholestyramine ( insoluble anionic exchange
resins)
3. Formulation Factors Affecting Oral
Absorption
• Role of dosage forms (outline)
– Solutions
– Suspensions
– Capsules
– Tablets
– In vitro correlation of drug absorption
• Disintegration testing ii. Dissolution
testing
 bioavailability
• The bioavailability of a drug to decrease in the
order
• Solution > suspension > capsule > tablet > coated
tablet.
• This order may not always be followed but it is a
useful guide.
• One example is the results for pentobarbital.
• Here the order was found to be
• Aqueous solution > aqueous suspension = capsule
> tablet of free acid form.
 Bioavailability
Bioavailability is defined as the fraction of unchanged drug
reaching the systemic circulation following administration
by any route.

20.10.09 66
 Bioavailability
Destroyed Not Destroyed Destroyed
in gut absorbe by gut wall by liver
Dose d
to
systemic
circulation
 Bioavailability of a drug
• The bioavailability of a drug (by a route other
than intravenous) is given by:
AUC (extra vascular)
• F= -----------------------------
AUC (intravenous)
• Amount of drug absorbed or reaching
plasma = F x Dose
• For example the oral bioavailability (F) of
digoxin (lanoxin) is 0.7
• For digoxin 250 ug given orally, the effective or
absorbed dose = 0.7 x 250 ug
= 175 ug
Plasma concentration Bioavailability
70
60 i.v. route
50 (AUC)o / (AUC)iv

40
30
oral route

20
10 Time (hours)
0
0 2 4 6 8 10
 Factors influencing bioavailability
• 1st pass hepatic metabolism:
GI absorption occurs through the portal circulation
which passes through the liver prior to reaching the
systemic circulation;

if drug metabolism occurs in the liver this process

diminishes the drug reaching the systemic
circulation.

1st pass metabolism is significant for a number of

drugs.
• Chemical instability:
Drugs for oral administration must be resistant to
gastric acid destruction (PCN) and degradative
enzymes in the intestine (Insulin)

• Nature of drug formulation:

Drug absorption can be effected by factors unrelated
to the drugs characteristics. Enteric coatings resist
gastric acid, polymerization, particle size, crystal
structure and binding agents can effect absorption
independent of active drug properties.
• Drug solubility:
Extremely hydrophilic drugs are poorly
absorbed across the lipid rich cell membrane.
Extremely hydrophobic drugs are also poorly
absorbed because they are insoluble in the
aqueous environment of the body.

Rapid absorption requires a combination of

lipophilic and aqueous solubility.
• http://www.dnatube.com/video/4815/Absor
ption-and-metabolism-of-orally-
administrated-drugs