Biopharmaceutics and Pharmacokinetics

Biopharmaceutics and Pharmacokinetics
(As per PCI Syllabus, for IV Pharm. D students)
By
Dr. Eswar Gupta Maddi,
Professor
Sir C. R. Reddy College of Pharmaceutical
Sciences, Eluru, A.P., India.
Learning to Read Correctly
1. First understand the topic / concept.
2. Prepare notes from one standard text book. Read the topic in text
book, close it and write your notes in your own language. You can
see the text book in the middle if you want.
3. Now learn your prepared notes. It will take around 2 to 3 hours for
one chapter for the first time.
4. When you try to recollect the lesson, the next day, you forget it.
Hence revision is required. Forgetting is a God’s gift, otherwise we
would have been very sad remembering all the bad things in our life.
5. Revise the lesson after one week. Now you will take 2 hours for
learning it.
6. Revise after another week. It will take now 1 hour.
7. On the exam day, you will take less than 1 hour for each chapter.
You can complete eight chapters in 5 to 6 hours.
8. If you start learning all eight chapters before the exam day, it will
take 16 to 24 hours and you will get confused.
9. So, u should not postpone learning. Learn the chapter, as soon as it

is completed in the class.
10. In case of chemistry, maths, etc. you have to practice the

structures and equations by writing them repeatedly.
Positive Auto Suggestions
Input is equal to output. Example: If u see a comedy movie u
laugh, if u see an emotional movie u may cry, if u see a violent movie u
may become violent. So, input is equal to output.
If u start your day by reading the below positive auto suggestions,

you will remain positive entire day and u will be successful in life.
By reading these auto suggestions daily once in the morning and

once in the night, you are programming your brain to think and act
positively in all situations.
1. I am an honest, cool, calm and relaxed person.
2. I am good in studies.
3. I always look for positive things in every person and every situation.
4. I will not run away from problems, I will solve them.
5. I am always with good and positive people.
6. I will always practice healthy habits.
7. I respect myself and others.
8. I always wish good for others.
9. I love my job and will work hard with dedication.
10. I will never postpone things.
11. I always do right things.
12. I give more than what I get to my family, organization and society.
13. I practice self-discipline and always finish what I start.
14. I take full responsibility for my thoughts and actions.
15. I am a courageous person.
16. I will improve daily.

17. I am always smiling.
18. I am happy with what I have.
19. I will always discuss, instead of arguing. (Argument is to find out

who is right, discussion is to find out, what is right.)
20. I will walk daily for one hour.
21. I will take only healthy food.
22. I will meditate daily for 30 minutes.
23. I will always teach moral values to children.
24. I am healthy and always energetic.
25. I will take care of my parents with respect, love and affection.
For further details on positive thinking, please read the book,

“You Can Win” written by Mr. Shiv Khera. It is a wonderful book that
everyone should read. So far, 26 lakhs books have been sold in sixteen
languages.
By following the principles of this book, you can achieve your goals and
live happily. It describes the tools, you need for success.
This book will help you to create an action plan for rest of your life. The
principles of this book are universal, you can apply in any situation,
anywhere.
Another book worth reading is, “How to win friends and Influence
people” by Mr. Dale Carnegie. It was first published in 1937 and is
translated into all languages spoken in the world. This book will help you
in maintaining a healthy relationship with everyone at work and family.
4.5 BIOPHARMACEUTICS AND PHARMACOKINETICS (THEORY)
PCI Syllabus
1. Biopharmaceutics: Introduction to Biopharmaceutics a. Absorption of drugs

from gastrointestinal tract. b. Drug Distribution. c. Drug Elimination.
2. Pharmacokinetics: Introduction to Pharmacokinetics. a. Mathematical

model b. Drug levels in blood. c. Pharmacokinetic model d. Compartment
models e. Pharmacokinetic study.
3. One compartment open model: a. Intravenous Injection (Bolus)

b. Intravenous infusion.
4. Multi compartment models. a. Two compartment open model. b. IV bolus, IV

infusion and oral administration.
5. Multiple – Dosage Regimens. a. Repetitive Intravenous injections – One

Compartment Open Model b. Repetitive Extra vascular dosing – One
Compartment Open model c. Multiple Dose Regimen – Two Compartment Open
Model.
6. Nonlinear Pharmacokinetics. a. Introduction b. Factors causing Non-

linearity. c. Michaelis-menton method of estimating parameters.
7. Non compartmental Pharmacokinetics. a. Statistical Moment Theory.

b. MRT for various compartment models. c. Physiological Pharmacokinetic
model.
8. Bioavailability and Bioequivalence. a. Introduction. b. Bioavailability study

protocol. c. Methods of Assessment of Bioavailability
References:
a. Biopharmaceutics and Clinical Pharmacokinetics by, Milo Gibaldi
b. Remington’s Pharmaceutical Sciences, By Mack Publishing Company, Pennsylvnia.
c. Pharmacokinetics: By Milo Glbaldi Donald, R. Mercel Dekker Inc.
d. Hand Book of Clinical Pharmacokinetics, By Milo Gibaldi and Laurie Prescott.
e. Biopharmaceutics and Pharmacokinetics; By Robert F Notari
f. Biopharmaceutics; By Swarbrick
Unit 1: Introduction to Biopharmaceutics
1.1: Journey of a tablet in the body:
1. When a tablet is taken orally, the following steps take place.
2. Tablets disintegrate (break) into granules.
3. Granules disintegrate to give small drug particles.
4. Drug particles dissolve in gastro intestinal fluids.
5. The dissolved drug crosses the gastro intestinal membrane and reaches the
blood. This is called absorption.
6. The blood carries the drug to all parts of the body. This is called distribution
of drugs.
7. The drug that reaches the liver is destroyed by its enzymes. This is called
metabolism of drugs. This is also called as first pass effect.
8. The drug that reaches the kidney is sent into urine. This is called excretion
of drugs. Excretion of drugs also takes place in saliva, sweat, etc.
9. Hence a drug undergoes absorption, distribution, metabolism and excretion
(ADME).
Sir C. R. Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India 1

1.2: Definitions:
1. Absorption: Movement of drug from site of administration into blood.
2. Distribution: Movement of drug from blood to all parts of the body is called
distribution.
3. Metabolism: Destruction of drug in the body by liver enzymes is called
metabolism.
4. Excretion: Removal of drugs from the body by kidney and other organs is
called excretion.
5. Biopharmaceutics: It is a study of the factors affecting the ADME of
drugs.
6. Pharmacokinetics: It deals with the speed of ADME of drugs. It is used to
fix dose and dosing interval.
Unit 1 (a): Absorption of drugs from Gastro Intestinal Tract (GIT)
1.3 Structure of cell membrane and its significance (importance) in drug

absorption:
1. The structure of cell membrane is shown below. It has a bi-layer of
phospho - lipid molecules.
2. This phospho-lipid molecule has a hydrophilic head and lipophilic tail.
3. The heads form the outer and inner boundary of cell membrane.
4. The tails are towards each other and form the lipophilic region of the
membrane.
5. Globular proteins are present between the phospho - lipid molecules as
shown in the diagram.
6. Pores of 4 to 10 angstroms are present in the cell membrane.

7. The cell membrane is a semi permeable membrane. It allows the transport
of molecules like glucose, amino acids, vitamins etc., and prevents the
entry of toxins and certain drugs
8. Hydrophilic drugs cannot cross the cell membrane easily.
9. Lipophilic drug molecules can easily cross the cell membrane
10. Inorganic ions and small water soluble molecules pass through the
pores present in cell membrane.
1.4 Mechanisms of drug absorption: The different mechanisms of drug

absorption are
a. Passive diffusion
b. Pore transport
c. Active transport
d. Ion pair transport
e. Endocytosis
a. Passive diffusion: 90 % of the drugs are absorbed by this mechanism. In

this mechanism, drug goes from higher concentration to lower concentration.
Example: When we take a tablet orally, the concentration of drug is more in
the GIT and less in blood. So, the drug moves from higher concentration to
lower concentration. This is called passive diffusion. The drug dissolves in
GIT fluids, crosses GI membrane and then goes into blood. The equation for
passive diffusion is given below.
dQ/dt = rate of drug diffusion
D = Diffusion coefficient of drug
A = Area of GIT membrane
Km/w = membrane water partition coefficient of drug

h = thickness of GIT membrane
CGIT – C = Difference in concentration between GIT and blood
Rate of drug diffusion (absorption), is directly proportional to D, A,
Km/w and concentration gradient. It is inversely related to thickness of
GIT membrane.

Once the drug reaches the blood, it is rapidly distributed to all parts of the
body. So, concentration of drug in blood is always less than the concentration
in GIT. This is called sink condition.
b. Pore transport: Small water soluble molecules like urea, sugar, pass
through the pores in cell membrane to blood. The pressure of GIT fluids is
responsible for pore transport.
c. Active transport: The GIT membrane has carriers. These carriers attach to
drugs and carry them to other side of membrane and leave them in blood.
Then, they return to the GIT side to carry another drug molecule. This is
called active transport or carrier mediated transport.
d. Ion pair transport: Negatively charged carriers attach with positively charged
drug molecules and transport them. This is called ion pair transport.
e. Endocytosis is cell eating. The GIT membrane engulfs the drug and releases it
on other side.

1.5: Biological Factors affecting absorption of drugs from GIT: The various
factors affecting absorption of drugs are discussed below.
1. Area of G.I.T: Stomach has less surface area when compared to small
intestine. Area of small intestine is almost equal to a tennis court. This is
due to presence of villi in the small intestine. Hence absorption of drugs will
be more in small intestine than in stomach.
2. The area of large intestine and rectum is less and absorption of drugs will
be less in this area.
3. The pH of GIT, pKa, and lipophillicity of drug affects absorption of drugs.
This is explained by pH partition theory.
4. Unionized form of drug is lipophillic and absorbed easily in GIT. If drug is
ionized, it is poorly absorbed.
5. The extent of ionization of a drug depends on its pKa and pH at site of
absorption and is given by Henderson- Hasselbalch equation.
6. pH of the stomach is around 1 to 3, weakly acidic drugs are un ionized

here and absorption will be fast. This is because un ionized drug molecules
are more lipophillic and can easily cross biological membranes.
7. pH of the intestine is around 7.4, weakly basic drugs are un ionized here
and absorption will be fast. This is because un ionized drug molecules are
more lipophillic and can easily cross biological membranes.
8. Very weak acidic and very weak basic drugs are unionized at all pH values
and are absorbed along the entire GIT.
9. Strongly acidic and strongly basic drugs are ionized at all pH values and
are poorly absorbed in GIT.
10. A drug should have hydrophilic nature to dissolve in G.I.T fluids and
lipophillic nature to cross GIT. Lipophillic nature can be measured using
octanol water partition coefficient experiments. Octanol represents the
GIT membrane.
11. A drug should have an optimum Ko/w value of 1000 / 1 for dissolution
and absorption in GIT.

12. If a drug is strongly hydrophilic, it will dissolve in GIT fluids but will not
cross GIT easily.
13. If a drug is strongly lipophillic, it will dissolve with difficulty in GIT
fluids. It accumulates in the GIT membrane because of its high lipophillic
nature.
14. Food may alter the absorption of drugs. Example: Milk reduces
absorption of iron. Vitamin C increases the absorption of iron.
15. Gastro intestinal motility: If G.I motility is more, drug absorption may
get reduced. Example: In diarrhea, absorption of drugs will be reduced

1.6 Physico - chemical factors of drug affecting drug absorption and
bioavailability:
1. Drug solubility: If a drug has good solubility in water, it will have good
dissolution rate and bio availability will be good. A drug should have a
minimum of 1 % solubility in water to avoid bio availability problems.
2. Particle size of the drug: Fine drug particles have more surface area and
dissolve fast. So bio availability will be good. Example: Tetracycline and
chloramphenicol have been micronized to improve dissolution rate and
bio availability.
3. Polymorphism: When a drug exists in more than one crystalline form, it is
called polymorphism. Polymorphs have same medicinal action but different
solubility and dissolution rate. Example: Chloramphenicol palmitate exists
as crystalline form A, B and C. Polymorph B has good bio availability.
4. Amorphism: Drugs can exist in crystalline form and in amorphous form
(no crystalline structure). Example: Amorphous novobiocin is 10 times
more soluble than crystalline form.
5. Hydrates: When water is trapped within the crystalline structure of drug,
it is called hydrate. Example: Anhydrous ampicillin has more solubility
than ampicillin tri hydrate.
6. Salt form of drug: Most of the drugs are weak acids or weak bases and
have poor solubility in water. Their salts have good solubility, dissolution
rate and bioavailability. Example: Tetracycline hydrochloride has better
solubility than tetracycline.
1.7 Pharmaceutical factors / Dosage form factors / Formulation factors

affecting drug absorption and bioavailability:
1. Type of dosage form: The bioavailability of a drug depends on the type of
dosage form. Example: Bioavailability is more from elixirs and syrups
when compared to tablets. The bioavailability of drug from various dosage
forms is in the below order.
2. Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated
tablets > Sustained release products.
3. Manufacturing process: Bioavailability of a drug depends on the
manufacturing method. Example: Tablets made by direct compression
have more bioavailability than tablets made by granulation method.

4. Additives used in the dosage form: If hydrophilic additives are used in
tablets, bioavailability will be good. If hydro phobic additives are used,
bioavailability will be poor.
5. Binder: If a strong binder is added in a tablet, tablets will have more
hardness, tablets will not disintegrate quickly and bioavailability will be
less.
6. Disintegrants: If a weak disintegrant is used in tablets, they will not
disintegrate easily and bioavailability will be less.
7. Lubricants and glidants: They are hydrophobic in nature. If excess
lubricants and glidants are used in tablets, disintegration and dissolution
will be less and bioavailability of drug will be less.
1.8: First pass effect and its significance:

1. It is also called first pass metabolism or pre systemic metabolism.
2. When a tablet is taken orally, drug dissolves in GIT fluids. After absorption,
the portal vein carries the drug first to the liver. The liver is rich in
enzymes and converts some amount of the drug into metabolites. This
bio transformation is called first pass effect.
3. Enzymes in the GIT fluids, enzymes in the GIT membrane and liver
enzymes are responsible for first pass effect.
4. Example: Morphine, diazepam, alcohol are metabolized in liver.
1.9: Rate limiting steps in drug absorption:

1. The slowest step in a process is called rate limiting step.
2. The speed of the entire process depends upon the rate limiting step.
3. When a tablet is taken orally, the following steps take place.
4. Disintegration of tablet into granules.
5. Granules disintegrate to give fine drug particles.
6. Dissolution of drug particles in gastro intestinal fluids.
7. The dissolved drug crosses the gastro intestinal membrane and reaches the
blood. This is called absorption.
8. Dissolution is rate limiting step for poorly water soluble drugs.
9. Absorption is rate limiting step for drugs having good solubility in water.

1.10: BCS classification of drugs:
1. BCS means biopharmaceutics classification system of drugs.
2. After dissolution in GIT fluids, drugs have to cross the GI membrane into
blood. This is called permeability.
3. Basing on solubility and permeability nature of drug, the BCS has four
classes of drugs.
4. Class 1: High Solubility – High Permeability, Ex: Chloroquine phosphate.
5. Class 2: Low Solubility – High Permeability, Ex: Azithromycin
6. Class 3: High Solubility – Low Permeability, Ex: Aspirin
7. Class 4: Low solubility – Low permeability, Ex: Cefixime
8. A drug substance is considered highly soluble when the highest dose
strength is soluble in 250 ml or less of aqueous media over the pH range of
1-7.5.
9. A drug substance is considered to be highly permeable when 90 % of dose
gets absorbed in humans.
10. Class I drugs can be formulated as oral tablets, capsules, solutions etc.,
because they have good solubility and permeability.
11. Class II drugs have to be modified to improve their solubility and
dissolution rate, then they can be formulated as tablets and capsules etc.
12. As class III and IV have poor permeability, they have to be formulated
as injections.

1.11: Compendial methods / Official / Pharmacopeia methods of
dissolution testing of different dosage forms:
1. The pharmacopeias describes the dissolution testing equipment and
procedures for tablets, capsules and other dosage forms.
2. The widely used dissolution test apparatus (USP) for various products are
basket apparatus, paddle apparatus and reciprocating cylinder apparatus.
3. Type I is basket apparatus. It has a glass or plastic bowl for holding
1000 ml of dissolution fluid. This bowl is immersed in a water bath which
maintains a temperature of 37 OC. A 40 mesh basket attached to a motor is
dipped in the dissolution fluid. One tablet or capsule is taken in the basket
and is dipped in dissolution media. Basket is rotated at the specified RPM.
Samples are taken at different time intervals for analysis. The % of drug
dissolved from tablets should meet the I.P. specifications.
4. Type II is paddle apparatus. It has a bowl for holding 1000 ml of dissolution
fluid. This bowl is immersed in a water bath which maintains a temperature
of 37 OC. A paddle attached to a motor is dipped in the dissolution fluid. It
is rotated at the specified RPM. One tablet or capsule is added to the
dissolution media and samples are taken at different time intervals for
analysis. The % of drug dissolved from tablets should meet the
specifications in pharmacopeia.
Apparatus 1: Basket type Apparatus II: paddle type

Unit 1 B: Distribution of Drugs
1.12: Introduction to distribution of drugs:
1. The blood carries the drug to different parts of the body as shown below.
2. Distribution of drug from blood to tissues is a reversible process.

3. Distribution is a passive process, and takes place from higher
concentration to lower concentration.
4. Initially, the blood concentration is high and tissue concentration is low.
Hence drug moves from blood into tissues until equilibrium is obtained.
5. The drug in the blood also undergoes elimination from the body by kidneys.
As a result drug concentration in blood decreases.
6. Hence the drug comes back from the tissues (high drug concentration) to
blood (low drug concentration).
7. Hence distribution of drugs between blood and tissues is a reversible
process.
1.13: Physiological Barriers for Drug Distribution:

1. The different barriers for drug distribution are blood brain barrier,
blood – cerebrospinal fluid barrier and blood placenta barrier.
2. Blood capillaries carry blood to all tissues. The blood capillary walls are
very thin and are made up of a single layer of endothelial cells. Drugs
easily cross this thin layer and enter into the tissue.
3. The blood capillaries of the brain have a layer of endothelial cells with tight
junctions. They are surrounded by astrocytes as shown in the below
figure. This layer of endothelial cells with astrocytes is called blood brain
barrier.

4. The BBB is highly lipophillic in nature and only small, lipophillic drugs
can pass through the BBB by passive diffusion.
5. The blood – brain barrier allows the passage of water, some gases,
lipid - soluble molecules by passive diffusion, and selective transport of
molecules such as glucose, vitamins, hormones and amino acids that are
necessary to the brain.
6. Example: Penicillin’s cannot cross BBB.
7. Blood cerebro spinal fluid barrier: The choroid plexus of the CNS produce
the CSF.The choroid plexus cells have tight junctions and do not allow
transport of drug molecules from blood into CSF.
The placental membrane separates the mother blood capillaries and fetal
blood vessels. Many drug molecules up to a molecular weight of

1000 Daltons cross this membrane and reach the fetus. This barrier is
not effective like BBB.
1.14: Factors Affecting Distribution of Drugs: The various factors

influencing distribution of drugs are
1. Physico – Chemical Properties of drug:
a. Drugs with molecular weight less than 500 Daltons easily cross biological
membranes by passive diffusion.
b. If drug molecule is ionized at blood pH, it will have poor tissue
permeability. Example: Penicillin is ionized at blood pH and cannot cross
blood brain barrier.
c. If drug molecule is un-ionized at blood pH, it will have good tissue
permeability. Example: Thiopental is un-ionized at blood pH and can easily
cross blood brain barrier.
d. Lipophillic drugs can easily cross biological membranes. Example:
Thiopental is highly lipophillic and distributes 80 times faster than salicylic
acid into CSF (cerebro spinal fluid).
2. Nature of tissue membrane: Distribution of drugs depends on the nature of
tissue membrane. Example: BBB is highly lipophillic, only highly lipophillic
drugs can cross the BBB. Example: Thiopental can cross BBB but
penicillin cannot cross BBB.
3. Organ size / Tissue size and blood perfusion rate:
a. Distribution of a drug to a particular organ depends on its tissue size and
blood flow.
b. Lungs, kidney, liver, heart and brain have high blood flow.
c. Muscles and skin have medium blood flow.
d. Fat and bone have poor blood flow.
e. Greater the speed of blood flow, greater will be the distribution.
4. Protein binding of drugs:
If the drug is highly bound to albumin in blood, its distribution will be less.
Proteins cannot cross biological membranes and hence protein bound drug
also cannot cross biological membranes.

5. Tissue binding of drugs:
a. If the drug is highly bound to tissue components, accumulation will take
place in that tissue.
b. Example: Tetracycline binds with calcium in bones and teeth.
c. Example: Thiopental accumulates in adipose tissue.
6. Age:
a. BBB is poorly developed in infants and drugs easily cross them.
b. Fat content is high in infants and elders and this affects drug distribution.
c. Proteins are low in infants and elders and affects drug distribution.
7. Pregnancy: In pregnancy, fetus is another compartment into which drugs
can be distributed by crossing placental barrier.
8. Obesity: In obese persons, fat tissue is more and lipophillic drugs
accumulate in fat tissue.
9. Diet: A diet rich in fats will increase fatty acid levels in blood and affect
protein binding of drugs. This will affect drug distribution.
10. Disease states: Altered albumin levels, altered blood flow and altered
tissue pH influence distribution of drugs. Example: In meningitis, BBB
becomes more permeable to polar antibiotics like penicillin.
11. Drug interactions: They alter protein binding and distribution of drugs.
1.15: Volume of distribution Vd:

1. It gives an idea about the distribution of drug in the body.
2. It is defined as hypothetical volume of body fluid in which the drug is
distributed.
3. Vd = Dose / C0
4. The body water is made up of three compartments
a. Blood : 6 liters
b. Extra cellular fluid : 12 liters
c. Intracellular fluid : 24 liters
d. Total : 42 liters
5. If the drug is highly protein bound, it will be present in the blood without
being distributed, so plasma concentration is very high and Vd will be less.
Example: Vd of warfarin is 10 liters.
6. If the drug accumulates in a tissue, plasma concentration will be very less
and Vd will be high. Example: Vdof Chloroquine is 15000 Liters.

1.16: Protein Binding of drugs:
1. When a drug forms a complex with proteins in the blood, it is called
protein binding.
2. Proteins are very large molecules and cannot cross biological membranes.
Hence protein bound drugs also cannot cross biological membranes.
3. Hence protein bound drugs are not distributed / metabolized /
eliminated from the body.
4. Only the free drug is distributed / metabolized / eliminated from the body.
5. Half-life of protein bound drugs is high.
6. Protein binding is reversible. Weak bonds such as hydrogen bonds,
hydrophobic bonds, Van Der Waals forces are responsible for protein
binding.
7. Example: Warfarin, diazepam, digitoxin binds to albumin in blood.
8. Glycoproteins, lipo proteins, globulins and hemoglobin are also involved
in protein binding of drugs.
1.17: Binding of drugs with albumin:

1. Human serum albumin (HSA) is a very large molecule. It has a molecular
weight of 65000 Daltons.
2. It is present in large quantities in blood.
3. Many drugs bind with albumin.
4. HSA has four different binding sites.
5. Site I – Warfarin binding site – NSAIDS and phenytoin bind at this site.
6. Site II – Diazepam binding site – Benzodiazepines bind at this site.
7. Site III – Digitoxin binding site.
8. Site IV – Tamoxifen binding site.
9. A drug can bind to more than one site. In such cases, the main binding site
is called primary binding site and the other site is called secondary site.
10. If two drugs bind to the same site, there will be competition between the
two drugs for binding.

1.18: Tissue Binding of Drugs:
1. A drug can bind to tissues also.
2. If binding occurs in tissues, drug gets accumulated in the tissue and acts as
a store house for drugs. Sometimes toxic reactions may be seen.
3. Thiopental accumulates in adipose tissue.
4. Generally tissue binding is reversible, but sometimes it may be
irreversible.
5. Example: paracetamol, chloroform bind irreversibly with liver tissue.
6. If a drug undergoes protein binding and tissue binding, there will be
competition between them for drug.
7. The order of binding in tissues is liver > kidney > lung > muscle.
8. Examples: Liver – paracetamol, chloroform.
9. Lungs – Anti histamines.
10. Kidneys – heavy metals like lead, mercury, etc.
11. Skin – Chloroquine, phenothiazines.
12. Eye - Chloroquine, phenothiazines.
13. Hair – arsenicals, chloroquine, phenothiazines deposit in hair shafts.
14. Bones – tetracycline, lead.
15. Fats – lipophillic drugs like thiopental and pesticides like DDT.
16. Nucleic acids – DNA interacts with chloroquine and quinacrine.
1.19: Factors affecting protein binding of drugs:

1. Drug related factors:
a. As concentration of drug increases, protein binding increases until
proteins are saturated.
b. Protein binding is more for lipophillic drugs.
c. Acidic drugs bind to albumin.
d. Basic drugs bind to globulins.
e. Neutral and un ionized drugs bind to lipo proteins.
f. Some drugs have affinity for a particular tissue. Example: Digoxin has
more affinity for proteins of cardiac muscle.
2. Tissue related factors:
a. Lipoproteins and adipose tissue bind with lipophillic drugs.
b. As concentration of albumin is more in blood, protein binding is more in
blood.

3. Drug interactions:
a. If two drugs bind to the same site, there will be competition between the two
drugs for binding.
b. One drug may displace another drug from albumin binding site.
c. Example: Phenyl butazone displaces warfarin from albumin. This
increases free drug concentration of warfarin and may cause toxic effects.
d. This interaction is called displacement interaction.
e. Warfarin is called displaced drug and phenyl butazone is displacer.
4. Patient related factors:
a. With age, protein content varies and protein binding changes.
b. In new born and elders, protein content is less and protein binding is less.
c. In disease states like CCF, burns, liver diseases, kidney diseases, surgery,
cancer, protein content is less and protein binding is less.
1.20: Importance of protein binding of drugs:

1. Distribution: Due to protein binding, only the free drug is available for
distribution and elimination. When free drug has been eliminated from the
body, the protein drug complex dissociates and free drug is available for
distribution and elimination. In this manner, the free drug is released from
protein drug complex for long periods of time. The complex acts as a store
house for drug. Hence half-life of protein bound drugs is high.
2. Elimination: Only free drug can be eliminated from the body by kidneys. As
a result elimination of protein bound drugs is slow.
Example: Tetracycline – 65% protein bound – half life – 8.5 hours.
Example: Doxycycline – 93% protein bound – half life – 15 hours.

Unit 1 C: Metabolism and Excretion of drugs
1.21: Introduction on drug metabolism:
1. The liver enzymes convert the drug into simple water soluble molecules.
This is called hepatic metabolism or bio-transformation.
2. Drug + enzyme Metabolite
3. Most of the drugs are lipophillic and stay in the body for long periods of
time. So, the body converts them into simple hydrophilic substances so
that they are easily eliminated in urine.
4. Example: Phenytoin is converted into p – hydroxy phenytoin.
5. Example: Diazepam is is converted into oxazepam.
6. Metabolism by liver is called hepatic metabolism.
7. Metabolism by other organs is called extra hepatic metabolism.
8. There are two pathways for drug metabolism, phase I reactions and phase II
reactions.
1.22: Phase I reactions:

1. Phase I reactions are known as functionalization reactions. In these
reactions, a polar functional group like –OH, - NH2, - SH, -COOH, is
introduced in the drug molecule.
2. Phase I reactions are done by microsomal and non-microsomal
enzymes.
3. Phase I reactions include oxidation, reduction or hydrolysis.
4. Oxidative reactions are catalyzed by mixed function oxidase enzymes.
5. Reduction reactions: Aliphatic aldehydes, aromatic aldehydes, acids are
reduced by enzymes called aldo – keto reductases.
6. Ester drugs are hydrolyzed by esterase enzymes.
7. Amide drugs are hydrolyzed by amidase enzymes.
8. Examples of phase I reactions are given below.

9. Oxidation Phase I reactions:
S.NO Reaction Reaction Pathway Example
1 Aromatic Phenylbutazone to
hydroxylation oxy phenyl butazone
2 Aliphatic Pentobarbital
hydroxylation
3 Oxidative Amphetamine
deamination
4 N–dealkylation Morphine
5 O-dealkylation Phenacetin
6 Alcoholic Ethanol
Oxidation
7 Aldehyde Acetaldehyde
oxidation
10. Reduction Phase I reactions:

1 Azo Sulfasalazine
reduction
2 Nitro Chloramphenicol
reduction
3 Aldehyde Chloralhydrate
reduction
11. Hydrolytic Phase I reactions:
1 De esterfication Procaine
2 De amidation Lidocaine

1.23: Phase II reactions:
1. The drug or metabolite obtained in phase I reaction is subjected to phase II
reaction. In these reactions, a small polar group like glucuronic acid,
sulfate, glycine etc., are attached to the phase I product.
2. The phase II product is called conjugate, and hence these reactions are
called conjugation reactions.
3. Phase II products are more water soluble than phase I products and are
easily eliminated in urine.
4. Enzymes of phase II reactions are called transferases, because they transfer
a polar group to the phase I metabolite.
5. Glucuronidation is a common phase II reaction. Glucuronic acid is available
in the liver due to glucose metabolism.
6. Uridine di phosphate glucuronic acid (UDPGA) conjugates with a number
of drugs / metabolites under the influence of enzyme glucuronyl
transferase.
7. Glycine and glutamine conjugation reactions occur with drugs or their
phase I metabolites to form amides by trans acylase enzymes.
8. Gluthathione conjugation reactions occur by gluthathione transferase
enzymes.
9. Sulfate conjugation reactions occur by sulfo transferase / sulfo kinase
enzymes.
10. Methylation conjugation reactions occur by methyl transferase
enzymes.
11. Acetylation conjugation reactions occur by acetyl transferase enzymes.
S.NO Reaction Examples

1 Glucuronidation Salicylates, oxazepam, sulfamethoxazole
2 Glycine conjugation Salicylic acid, fenfluramine
3 Glutathione conjugation Paracetamol
4 Sulfate conjugation Steroids
5 Methylation Oxprenolol
6 Acetylation Procainamide

1.24: Factors influencing metabolism of drugs:
1. Physico chemical properties of the drug: Size of the molecule, pKa, acidity /
basic nature, lipophilicity influence the interaction of drug with enzyme.
As a result metabolism is affected.
2. Drug interactions: In multiple drug therapy, one drug increases or
decreases the metabolism of other drugs.
a. When a drug increases the metabolism of other drugs it is called enzyme
induction. Example: Barbiturates increase the metabolism of
anti-coagulants. Induction occurs by increasing the synthesis of enzymes
responsible for drug metabolism.
b. When a drug decreases the metabolism of other drugs, it is called enzyme
inhibition. Example: Para amino salicylic acid decreases the metabolism
of phenytoin. Inhibition occurs by decreasing the synthesis of enzymes
responsible for drug metabolism.
3. Biological factors:
a. Qualitative differences are differences in the actual metabolic pathway.
This is due to genetic deficiency of a particular enzyme. Example: In man
and rabbit amphetamine is metabolized by oxidative deamination, where
as in rats aromatic oxidation is the main route.
b. Quantitative differences are differences in the extent of metabolism. This is
due to differences in quantity of enzyme present from person to person
and species to species. The metabolic pathway is same.
4. Drug metabolism variation in male and females is due to difference in their
hormones. Example: women metabolize benzodiazepines slowly than men.
5. Age: Enzyme content varies with age and metabolism varies.
a. In neonates (upto 2 months age), enzyme systems are not fully developed
and many drugs are metabolized slowly. Example: Caffeine has half-life of
4 days in neonates, it is 4 hours in adults.
b. As age increases, metabolizing capacity increases.
c. In very elderly persons, the liver size is reduced and enzyme activity is
decreased. Hence drug metabolism is reduced.
a. Diet: Protein rich diet increases enzymes in body and increases
metabolism of drugs. Deficiency of vitamins and minerals decrease activity
of enzymes.

6. Pregnancy: High levels of steroid hormones in last stages of pregnancy
reduce the activity of enzymes.
7. Disease states:
a. Any disease condition with liver will reduce activity of enzymes.
b. In congestive cardiac failure, blood flow to liver decreases and enzyme
activity is reduced.
8. Circadian rhythm: Variation in enzyme activity with light cycle is called
circadian rhythm. It has been found that enzyme activity is more in early
morning (6 to 9 a.m.) and minimum in afternoon (2 to 5 P.m.)
9. Route of administration: In oral route, first pass effect is seen. In I.V and
sublingual route first pass effect is not seen.
1.25: Introduction on Excretion of drugs:

1. It is a process by which the drugs and its metabolites are sent out of the
body.
2. Excretion of drugs is mainly done by kidneys and is called renal excretion.
Excretion by other organs like lungs, salivary glands, biliary system, sweat
glands, skin and intestine is called non renal excretion.
1.26: Renal excretion of drugs:

1. Excretion of drugs by kidneys is called renal excretion.
2. Nephron is the basic functional unit of kidney. Each kidney has around one
million (10 lakhs) nephrons.
3. Each nephron has glomerular capsule, proximal tubule, loop of Henle,
distal tubule and collecting tubule.
4. The steps in urinary excretion of drugs are glomerular filtration, active
tubular secretion and tubular reabsorption.
Glomerular filtration:
a. Every minute, around 1.2 liters of blood goes to the kidney and gets
filtered in the glomerulus.
b. Filtration takes place through the semi permeable walls of glomerular
capsule. RBC, WBC, platelets, albumin and globulin are not filtered.
c. The filtrate contains water, minerals, salts, glucose, hormones, drugs
and their metabolites.

d. The filtrate volume is 130 ml/min that is 180 liters per day. This value
of 130 ml/min is called glomerular filtration rate (GFR).
e. Even though filtrate volume is 180 liters per day, only 1.5 liters urine is
excreted per day. Remaining water is reabsorbed from the renal tubules.
f. Creatinine is excreted by glomerular filtration only and is used to estimate
GFR. If GFR is 130 ml/minute, it indicates that the person kidney is
functioning properly.
Active tubular secretion:

a. As blood does not stay for sufficient time in glomerulus, the drugs are
not completely removed by filtration.
b. Drugs that have escaped in the above filtration step, undergo active
secretion in proximal renal tubule by carriers.
c. Carrier systems are available for weakly acidic and basic drugs.
Tubular re absorption:
a. Tubular re absorption takes place in the entire renal tubule.
b. Drugs and other nutrients like glucose, electrolytes, vitamins, amino acids
that are required for the body undergo tubular re absorption by active or
passive process.
c. As most of the water filtered in glomerulus is reabsorbed in renal tubule,
the drug concentration in renal tubule is very high than that in blood,
hence passive diffusion of drugs from renal tubule to blood takes place.

1.27: Clearance:
1 Clearance is defined as the hypothetical volume of body fluids from
which the drug is removed completely.
2 Total body clearance = Renal clearance + hepatic clearance + lung clearance + biliary clearance .
3 Clearance = Total elimination rate /Cp

4 Renal clearance is defined as the hypothetical volume of body fluids from
which the drug is removed completely by kidneys.
5 ClR = Urinary excretion rate of drug / Cp
6 ClR = [Rate of drug filtration + rate of drug secretion –rate of drug re absorption] / Cp
7 The below table gives the relationship between renal clearance values and
mechanism of clearance.
S.NO Renal Mechanism Example
Clearance,
ml/min
1 0 Drug filtered and reabsorbed Glucose
completely
2 Less than 130 Drug filtered and partially reabsorbed Lipophillic
drugs
3 Greater than Drug filtered and secreted actively Polar, ionic
130 drugs
4 = 130 Drug is filtered only Creatinine,
inulin
5 650 (highest Clearance equal to renal plasma flow Iodopyracet
value) rate

1.28 Factors Affecting Renal Excretion of Drugs: The various factors
influencing renal excretion of drugs are
1. Physico – Chemical Properties drug:
a. Small drug molecules with molecular weight less than 500daltons are
easily filtered in glomerulus.
b. Hydrophilic drugs are easily excreted in urine. Unionized and lipophillic
drugs undergo re absorption in renal tubules. They stay for long time in the
body.
2. Plasma concentration of drug: If Cp is more, excretion rate of drug will be
more. More drug will be filtered in kidneys.
3. Distribution and binding characteristics of the drug: If a drug is highly
protein bound, it cannot be filtered in kidney and renal clearance will be
less. Example: Tetracycline is 93 % bound to plasma proteins; hence it has
low renal clearance.
4. Tissue binding of drugs:
a. If the drug is highly bound to tissue components, accumulation will take
place in that tissue. Example: Tetracycline binds with calcium in bones
and teeth.
b. Example: Thiopental accumulates in adipose tissue.
5. Old Age: In old age GFR decreases and renal tubular secretion is altered,
hence renal clearance is decreased.
6. New Born: In new born, renal function is 30 to 40 % less, hence renal
clearance is less.
7. Renal clearance is 10 % less in females than in males.
8. Drug interactions: Any drug interaction which alters protein binding, renal
blood flow, active secretion, urine pH, will alter renal clearance of drugs.
a. Diuretics increase urine flow rate and increase renal clearance of drugs.
b. Furosemide reduces protein binding of gentamycin in blood, so more
gentamycin is excreted in urine.
c. Acidification of urine with ascorbic acid or ammonium chloride increases
excretion of basic drugs.
d. Alkalinisation of urine with citrates, tartrates, bicarbonates, increases
excretion of acidic drugs.
9. Disease states: In kidney failure, renal elimination of drugs decreases.
Hence GFR should be determined using creatinine clearance. Dose should

be adjusted depending on creatinine clearance. If it is half of normal value of
130 ml/minute, reduce the dose by half.
1.29 Non Renal Routes of Drug Excretion: The other routes of excretion of
drugs are biliary excretion, pulmonary excretion, salivary excretion, mammary
excretion, skin or dermal excretion, GI excretion, genital excretion.
1.30 Biliary excretion of drugs / Entero hepatic cycling of drugs:

1. Bile juice is produced by liver and is stored in gall bladder.
2. It is secreted into the duodenum for digestion of fats. The bile flow rate is
0.5 to 1 ml per minute. 90 % of the bile acids are reabsorbed from the
intestine and is transported back to the liver for re secretion.
3. Drugs and their metabolites enter from the plasma to bile juice through
hepatocytes (liver cells). This bile juice carries the drug and secretes in
duodenum. Thus the drug comes out along with fecal matter. Some of the
drug is again reabsorbed from intestine into blood and goes back to the
liver. Again it is excreted by bile juice. This cycling of drugs is called
entero hepatic cycling of drugs.
4. Entero hepatic cycling is important for saving important substances such as
vitamin B12, vitamin D3, folic acid, steroid hormones, and bile salts in the
body.

1.31: Factors Affecting Biliary Excretion of Drugs: The various factors
influencing biliary excretion of drugs are
1. Physico – Chemical Properties drug:
a. Drug molecules with molecular weight greater than 500 Daltons are
excreted in bile.
b. Drug molecules with molecular weight less than 300 Daltons are excreted in
urine.
c. Drug molecules with molecular weight between 300 to 500 Daltons are
excreted in bile and urine.
2. Drug metabolism: Polar drugs are readily excreted in bile. Drugs are
metabolized in the liver and polar metabolites are produced. They are readily
excreted in the liver.
3. Miscellaneous factors: Age, sex, species differences, protein binding,
disease states and drug interactions influence biliary excretion of drugs.
a. High molecular weight drugs show good biliary excretion in rats, dogs and
hen. Biliary excretion is poor in rabbits, guinea pigs and monkeys.
b. In cholestasis, bile flow rate is reduced and biliary excretion of drugs is
reduced.
c. Orally administered drugs after absorption go to liver and are excreted more
in bile when compared to parenteral products.
d. Diet also influences biliary excretion of drugs. Protein and fat rich diet
increases bile flow.
Biliary Clearance: The ability of the liver to excrete the drug in the bile is
expressed as biliary clearance. Biliary clearance = Biliary excretion rate / Cp
1.32 Pulmonary excretion of drugs:

1. Gaseous and volatile substances such as general anesthetics are absorbed
through the lungs by simple diffusion. Similarly excretion of drugs through
the lungs is also possible. Pulmonary blood flow, rate of respiration,
solubility of volatile substance etc. influence pulmonary excretion of drugs.
2. Example: Alcohol is excreted via lungs slowly. Nitrous oxide has less
solubility in blood and is excreted rapidly.

1.33 Salivary Excretion of drugs and Salivary Cycling:
1. Excretion of drugs into saliva is a passive process and can be predicted by
pH partition theory. Un ionized, lipophillic drugs are readily excreted in
saliva. This depends on pKa of drug and pH of saliva and blood.
2. The s/p ratios have been found to be less than one for weak acids and
greater than one for weak bases. Basic drugs are excreted more in saliva as
compared to acidic drugs.
3. As s/p ratios are fairly constant for a drug, it can be used to determine
blood concentration from saliva concentration.
4. Example: Caffeine, theophylline, phenytoin are excreted in saliva.
5. Some drugs are actively secreted, example: penicillin and phenytoin.
6. Bitter after taste in the mouth of a patient is due to salivary excretion of
drugs. Some drugs inhibit salivary secretion and are responsible for dryness
of mouth.
7. Drugs excreted in saliva can undergo cycling as shown below.
1.34 Skin Excretion:

1. Drugs are excreted through the skin via sweat and follows pH partition
hypothesis. This is the reason for skin reactions and dermatitis.
2. Compounds such as benzoic acid, salicylic acid, alcohol and anti pyrine,
heavy metals like lead, mercury and arsenic are excreted in sweat.
1.35: Gastro intestinal excretion of drugs:
1. Excretion of drugs into the GIT occurs after parenteral administration, by
passive diffusion process. This is reverse process of GI absorption.
2. Orally administered drugs can also be reabsorbed and excreted in the GIT.
Drugs excreted in the GIT are reabsorbed into the systemic circulation and
undergo recycling.

Unit 2: Introduction to Pharmacokinetics
2.1: Basics of kinetics:
1. Kinetics deals with speed of a process. A process may be zero order or first
order.
2. If the speed of ADME does not depend on dose of the drug, it is called zero
order process. Example: Active absorption of riboflavin in GIT.
3. The equation for a zero order process is Ct = C0 – K0 t.
4. The time taken for half of the process to be completed is called half-life.
C0 = Initial concentration of reactants at zero time.

Ct = Concentration of reactants remaining at
time‘t’.
K0 = Zero order rate constant.
A graph of Ctand time will give a straight line with
a negative slope. Slope is equal to - K0. The Y
intercept is equal to C0.
5. If the speed of ADME depends on dose of the drug, it is called first order
process. Example: ADME of drugs.
6. The equation for a first order process is
log Ct = log C0 – [ K1 t/2.303 ].

7. The time taken for half of the process to be
completed is called half-life, t1/2 = 0.693/ K1
8. First order kinetics graph: A plot of log Ctand time

will give a straight line with a – ve slope equal to
– K1 / 2.303. The Y intercept is equal to log C0.
2.2: Introduction to Pharmacokinetics and its importance in Bio

availability and clinical practice / Concepts, definition and explanation of
terminologies used:
1. Pharmacokinetics is study of speed of ADME of drugs. This information is
used to fix dose and dosing time table.
2. The various important pharmacokinetic parameters of a drug are
absorption rate constant, absorption half-life, elimination rate
constant, elimination half-life, volume of distribution and clearance.

3. Example: Paracetamol biological half-life is 4 hours, so we take a
paracetamol tablet every 4 to 6 hours.
4. In pharmacokinetics, we give a tablet to a person, and collect his blood

samples, every one hour, until the drug is completely eliminated from the
body. Then, graphs are constructed to know the kinetics (speed) of
ADME.
5. The different pharmacokinetic parameters are calculated from graphs,
which will be useful for fixing dose and dosing time table.
6. Clinical pharmacokinetics: Application of pharmacokinetic principles for
fixing dose and dosing time tableinindividual patients.
7. Example: If a person has one damaged kidney, the dose will be reduced by
half.
8. Pharmacodynamics deals with concentration of drug in blood and its
pharmacological response.
9. Pharmacokinetics is a study of what the body does to the drug.
10. Pharmacodynamics is a study of what the
drug does to the body.
2.3: Mathematical model / Pharmacokinetic model / Compartment model

/ Pharmacokinetic study:
1. Pharmacokinetics is the study of speed of ADME of drugs.
2. If we know the speed of ADME, we can fix the dose and dosing interval
(dosage regimen) for a drug.
3. Example: Paracetamol biological half-life is 4 hours, so we take a
paracetamol tablet every 4 to 6 hours.
4. To calculate the pharmacokinetic parameters of a drug, we require
compartment models. There are mammillary compartment model and
catenary model.
5. Mammillary compartment model or satellite model: In this model, the body
is divided into one or more compartments. It is also called satellite model.
6. In one compartment model, the entire body is considered as a single
compartment.
7. In two compartment model, the body is divided into two compartments.
Brain, liver, blood, heart, kidney, lungs have high blood supply and is

considered as first compartment. The rest of the body is second
compartment.
8. In case of three compartment model, the body is divided into three
compartments, basing on blood supply.
9. Brain, liver, blood, heart, kidney, lungs – first compartment
10. Muscle tissue – second compartment.
11. Adipose tissue and bone tissue – third compartment.
12. The drug enters into the first compartment and distributes to other
compartments.
13. By dividing the body into compartments, calculation of pharmacokinetic
parameters become easy.
14. Catenary model: In this model, the compartments are joined to one
other like the compartments of a train. It is shown below.

2.4: Blood level curves:
1. A blood level curve is constructed by taking time on x axis and blood /
plasma drug concentration on y axis.
2. An IV injection or oral tablet is given to a human volunteer and his blood
samples are analyzed for drug concentration. Then the graph is constructed
by taking time on x axis and drug concentration on Y axis. The following
curves will be obtained.
3. Cp is concentration of drug in blood / plasma. After an IV injection, the
drug gets distributed to different parts of the body. Elimination of drug takes

place in the kidney and hence blood concentration of drug decreases. This
can be seen in the below graph.
4. In case of oral administration, the blood level curve is shown in the below
graph.
5. The tablet breaks into pieces and the drug dissolves in the GIT fluids. It gets
absorbed into blood.
6. Once the drug is absorbed into blood, elimination of drug also starts.
Initially absorption speed is greater than elimination speed, so the Cp
increases as shown in the graph.
7. After some time, absorption speed is equal to elimination speed and the
graph is flat at the top.
8. Later elimination dominates absorption and the graph shows a decrease in
Cp concentration.
9. The drug will show its action as long as the drug concentration is between
MEC (minimum effective concentration) and MSC (maximum safe
concentration).
Blood level curve after IV Blood level curve after oral tablet
administration administration
MEC = Minimum effective 1 – Absorption phase
concentration 2 – Post absorption phase
MSC = Maximum safe concentration 3 – Elimination phase

Unit 3: One compartment open model
3.1: One compartment open model – Intravenous injection (Bolus):
1. In this model, the entire body is considered as a single compartment.
2. A single dose is given intravenously. The drug is distributed in the body in

two to three minutes.
3. Blood samples are taken for analysis at different time intervals.
4. Zero order and first order graphs are drawn.
5. If we get a straight line in zero order graph, it indicates that the drug is
getting eliminated from the body according to zero order kinetics.
6. If we get a straight line in first order graph, it indicates that the drug is
getting eliminated from the body according to first order kinetics.
7. The elimination rate constant is found from the slope of the graph. If a
drug eliminates quickly from the body, elimination rate constant will be
high.
Zero Order: Slope = – KE First Order: Slope = – KE / 2.303

Cp = Plasma concentration at time t. KE = Elimination rate constant
8. Biological Half Life, t 1/2: The time taken for half of the dose to be
eliminated from the body is called biological half-life. In zero order
elimination, t ½ = C0 /2 KE,in first order elimination, t ½ = 0.693/KE.
9. If a drug eliminates quickly from the body, t½ will be less.

Example: Paracetamol half-life is 4 hours and diazepam half-life is 20
hours.

10. Clearance, CL: It gives an idea about the elimination of drug in the
body. It is defined as theoretical volume of body fluid from which the drug
is eliminated completely. CL = Elimination Rate/ Cp
11. If the clearance is more, it indicates that the drug is getting eliminated
quickly from the body. Example: Clearance of aspirin is 39 L/hr,
paracetamol is 20 L/hr.
12. Volume of Distribution, Vd: It gives an idea about the distribution of
drug in the body. It is defined as hypothetical volume of body fluid in which
the drug is distributed. Vd = Dose / C0
13. If the drug is present in the blood without being distributed, plasma
concentration is very high and Vd will be less.
14. If the plasma concentration is very less, Vd will be high. Vd of warfarin
is 10 liters, Vd of Chloroquine is 15000 Liters.
15. Area under the Curve, AUC: The area under the plasma concentration
versus time curve is directly proportional to the dose. Greater the dose,
greater will be the AUC. If dose is doubled AUC will also double.
16. AUC can be found by the following formulas.
17. AUC = C0 / KE = Dose / KE VD = Dose / CL
18. AUC is used to compare
bioavailability of different
products.
3.2: One compartment open model – Intravenous infusion:

1. In this model, the entire body is considered as a single compartment.
2. Drug is given intravenously for long periods of time.

3. Intravenous infusion is an example of zero-order absorption and first-order
elimination.
4. Blood samples are taken at different time intervals and they are analyzed for
drug concentration.

The plasma drug concentration at
any time after the start of an
intravenous infusion is given by the
following equation:
5. R is the zero-order rate of infusion (milligrams per min).
6. The various pharmacokinetic
parameters in this model are
calculated by drawing graphs
between log Cp and time t.
7. If the intravenous infusion is discontinued, the plasma drug concentration

decreases by a first order process. The elimination rate constant, KE, can be
obtained from the slope of the curve.
8. As the drug is infused, the plasma drug concentration increases to a
plateau, or steady-state concentration (CSS). Under steady-state
conditions, the rate of infusion equals the rate of drug elimination from the
body.
9. The plasma concentration at steady
state (Css) is given by the following
equation:
10. The rate of drug infusion (R) may be calculated from a rearrangement of
the above equation if the desired Css, the VD, and the KE are known.
11. A loading dose (DL) is given as an initial intravenous bolus dose to

produce the Css as rapidly as possible. The intravenous infusion is started at
the same time as the DL.
12. The time to reach Css depends on the elimination half-life of the drug.
Reaching Css without a DL takes around 6 half lives. Thus, for a drug with
an elimination t½ of 8 hrs, it will take 48 hours hrs, to reach Css if no
loading dose is given.
13. DL is calculated by the following equation:

The IV infusion keeps the plasma drug concentration between the minimum
toxic concentration (MTC) and the minimum effective concentration (MEC).
3.3 One compartment model extra vascular administration:

1. In this model, the entire body is considered as a single compartment. The
product is taken orally and there is an absorption step.
2. Blood samples are taken for analysis at different time intervals.

3. Once the drug is absorbed into blood, elimination of drug also starts.
Initially absorption speed is greater than elimination speed, so the Cp
increases as shown in the graph.
4. After some time, absorption speed is equal to elimination speed and the
graph is flat at the top.
5. Later elimination dominates absorption and the graph shows a decrease
in Cp concentration.
calculated by drawing graphs.
1 –Absorption phase
2 – Post absorption phase
3 – Elimination phase
MEC = Minimum effective concentration

MSC = Maximum safe concentration
6. Plasma Concentration Cp: The plasma concentration of drug at different
time intervals can be calculated using the below equation.
Cp = Plasma concentration of drug
F = Fraction of drug absorbed
D0 = Dose taken orally K E = Elimination rate constant

K A = Absorption rate constant Vd = Volume of distribution

7. Tmax: The time taken for peak plasma concentration is called tmax.Thetmax is
given by below equation.
A shorter tmax indicates, faster rate
of absorption.
8. Elimination rate constant:By drawing graph between log Cpand time we

get the below graph. The line 2 is the elimination phase. Slope of the line 2
is equal to– KE / 2.303.
10. Biological half-life: The time taken for half of the doseto be eliminated
from the body is called biological half-life. It is given by the equation
t½ = 0.693/KE.
11. Absorption rate constant: The absorption kinetics of a drug into blood
is given by the absorption rate constant. It can be determined by method of
residuals or feathering or peeling or stripping or curve fitting method.
12. Draw a graph using time and log Cp, we will get the below graph.
13. Line 1 represents the absorption phase.

14. Line 2 represents the elimination phase. Extend this line to cut y axis
(line 3). This line is called back extrapolated (extended) line.
15. Calculate the difference between points on extrapolated line 3
and corresponding points on line 1, we get residuals.
16. Plot a graph using time and residuals. We will get line 4. Slope of
this line is equal to – KA / 2.303.
17. Absorption Half Life, t 1/2: The time taken for half of the dose to be
absorbed into blood is called absorption half-life. t ½ = 0.693/ KA

18. Area Under the Curve: The rate and extent of absorption is called
bio availability. It is measured using the area under the curve. The greater
the AUC greater the bio availability.The AUC is measured by trapezoid rule.
19. Area of trapezoid = W (a+b) /2
20. Calculate the tail area using the formula, Area of tail = Clast / KE
Fraction of drug absorbed F :

It is calculated using the below
formula. If F is more, it indicates
that bio availability of the tablet is
more.
21. The volume of distribution and clearance are given by the below
formula.
3.4: Wagner Nelson Method:

1. The absorption rate constant can also be determined by Wagner Nelson
method.
2. Absorption of drugs may be zero order or first order.
3. This method requires that elimination of drugs follow first order kinetics.
4. In this method, the cumulative amount of drug absorbed into the blood at
different time intervals is calculated.
5. Now the amount of drug remaining to be absorbed (DRA) is calculated.
6. If a graph of DRA and time gives a straight line, it indicates that the drug is
absorbed according to zero order kinetics.

7. If a graph of Log DRA and timegives a straight line, it indicates that the
drug is absorbed according to first order kinetics.
8. From the slope of the graphs KA can be calculated.
Slope = - KA Slope = - KA / 2.303

Unit 4: Multi Compartment model
4.1 Two compartment model - IV bolus:

1. In this model, the body is divided into two compartments.
2. Brain, liver, blood, heart, kidney, lungs have high blood supply and is
considered as first compartment. The rest of the body is second
compartment.
3. A single dose is given intravenously.

4. The drug enters into the first compartment, distributes quickly to all the
tissues of the first compartment, because the blood supply is very high.
Simultaneously elimination also starts from the first compartment.
5. The drug distributes slowly from first compartment to second compartment
in a reversible manner.
6. Blood samples are taken at different time intervals. They are analyzed for
drug concentration.
7. A plot of log Cp versus time is shown below.
8. Line 1: The Cp falls sharply because the drug is getting distributed from
first compartment to second compartment and getting eliminated at the
same time.
9. At time x in above graph, distribution is complete.
10. Line 2: Distribution is complete, this line represents only elimination
phase.
11. Line 3: This line shows the increase in concentration of drug in tissue
compartment. As drug comes from first compartment to second

compartment concentration of drug increases.
12. Line 4: As concentration of drug decreases in central compartment drug
goes back from second compartment to first compartment. Hence its
concentration decreases with time.
13. It is assumed that distribution and elimination follows first order
kinetics.
14. The various pharmacokinetic parameters in this model are calculated by
drawing graphs.
15. The equation for the below graph is Cp = A e –αt +Be –β t
Cp = Plasma concentration at time t A,B = Hybrid coefficients
α = hybrid first order rate constant β= hybrid first order rate constant for
for distribution process elimination process
16. The slope of line 2 in the graph is equal to – β / 2.303.

17. By extrapolating line to cut y axis, we get y intercept equal to B.
18. Method of residuals can be used to determine A and α. Calculate the
difference between points on extrapolated line 3 and corresponding points
on line 1, we get residuals.
19. Plot the residuals versus time, and we get line 4.
20. The y intercept of line 4 is equal to A and slope is equal to – α / 2.303.
21. Once A, B, α, and β are known, other pharmacokinetic parameters can
be calculated.
22. Volume of central compartment = Vc = Dose/ A+B

23. , 24. CLt = Dose / AUC
4.2: Two compartment model- Extra vascular administration:

considered as first compartment or central compartment. The rest of the
body is second compartment.
3. A single dose is given orally and there is an absorption step.

4. It is assumed that absorption, distribution and elimination of drug follow
first order kinetics in the body.
5. Elimination is from central compartment only.
6. The drug is absorbed into the first compartment, distributes quickly to all
the tissues of the first compartment, because the blood supply is very high.
Simultaneously elimination also starts from the first compartment.
7. The drug distributes slowly from first compartment to second compartment
in a reversible manner.
drug concentration.
9. In this model the plasma concentration is given by the below tri exponential
equation.
10. Cp = N e – Ka t +Le –αt +Me –β t
Cp = Plasma concentration at time t L, M, N = Hybrid coefficients
α = hybrid first order rate constant β= hybrid first order rate constant for
for distribution process elimination process
Ka = absorption rate constant

11. A plot of log Cp versus time is shown below. The three exponents can be
found out by step wise application of method of residuals.
12. Line 1: The Cp rises because the drug is getting absorbed.

Simultaneously drug is distributed and eliminated, but since absorption
dominates, line 1 shows an increase in Cp with time.
13. Line 2 represents the elimination phase of the drug and the slope of line
2 in the above graph is equal to – β / 2.303.
14. Back extrapolate line 2, we will get line 3. It cuts the y axis and y
intercept is equal to log M.
15. Find the difference between points on line 1 and line 3 and plot these
residuals, we will get curve 4. It is first residual curve. The slope of the
terminal phase line 5 is – α / 2.303.
16. Back extrapolate line 5 to cut y axis, the y intercept is equal to log L.
17. The back extrapolated line is called line 6. It is back extrapolated
distribution curve.
18. Using curve line 6 and 4 calculate residuals and plot a second residual
line. The slope of this residual line 7 is = - Ka/2.303.
19. Hence curve 1 has been resolved into three lines 3, 6 and 7, to find out
the pharmacokinetic parameters.

4.3: Two compartment model IV Infusion:
considered as first compartment or central compartment. The rest of the
body is second compartment.
3. A single dose is given by constant rate IV infusion and there is no

absorption step.
4. It is assumed that distribution and elimination of drugs follow first order
kinetics in the body.
5. Elimination is from central compartment only.
6. The drug distributes quickly to all the tissues of the first compartment, and
slowly to the tissues of the second compartment.
7. Simultaneously elimination also starts from the first compartment.
drug concentration.
9. Initially the blood concentration will be zero at zero time. As infusion
continues, drug concentration in blood rises. After some time, steady state is
achieved. Under steady-state conditions, the rate of infusion equals the rate
of drug elimination from the body.
10. At steady state, there is equilibrium between drug in first and second
compartment.
The plasma drug concentration at
steady state after the start of an
intravenous infusion is given by the
following equation:
14. R is the zero-order rate of infusion given in units as milligrams per
hour or milligrams per minute. Vc is volume of the central compartment
and Ke is the elimination rate constant of drug.

calculated by drawing graphs
between log Cp and time t.
16. If the intravenous infusion is discontinued, the plasma drug

concentration decreases by a first order process. The elimination rate
constant, KE, can be obtained from the slope of the declining plasma drug
concentration versus time curve.
17. A loading dose (DL) is given as an initial intravenous bolus dose to
produce the Css as rapidly as possible. The intravenous infusion is started at
the same time as the DL.
18. The time to reach Css depends on the elimination half-life of the drug.
Reaching Css without a DL takes around 6 half lives. Thus, for a drug with
an elimination t½ of 8 hrs, it will take 48 hours hrs, to reach Css if no
loading dose is given.
19. DL is calculated by the following equation:

Unit 5: Multiple – Dosage Regimens
5.1: Kinetics of Multiple Dosing / Dosage regimens /Pharmacokinetics of
a drug following repeated administration (IV / extra vascular):
1. Dosage regimen is the manner in which a drug is taken.
2. Example: Paracetamol tablets are taken four times a day.
3. In chronic diseases, the same dose is administered repeatedly at fixed
dosing intervals. Dose and dosing interval should be designed basing on the
pharmacokinetic parameters of the drug and disease state of the patient.
4. Example: In diabetes, B.P, tablets have to be taken daily at a definite time in
the day.
5. The Cp versus time graph on repeated administration is given below.
6. Generally, the next dose is administered before the previous dose is

completely eliminated.
7. The dosing interval is equal to the half life of the drug. For example half life
of paracetamol is four hours. So every four hours, a paracetamol tablet is to
be taken.
8. On repeated administration drug accumulates in the body. As concentration
of drug increases in the blood, elimination speed also increases according to
first order kinetics.
9. When the rate of administration is equal to rate of elimination, steady state
reaches in the body. Generally steady state is reached after five to six half
lives.
10. At steady state, the amount of drug eliminated during one dosing interval
is equal to the dose administered.
11. At steady state, Cp values will fluctuate between Cpss min and Cpss max.
12. In repeated IV administration, steady state Cpss min and Cpss max can be
calculated using the below equations.
D = dose and τ = dosing interval.

13. In repeated EV administration, steady state Cp min and Cp max can be
calculated using the below equations.
15. In case of emergency a loading dose is given followed by maintenance dose.

IV administration: Loading dose = Cp desired x Vd
EV administration: Loading dose = Cp desired x Vd / F
16. The average steady state plasma concentration is directly proportional to
dosing rate FD/ τ.
17. By increasing F, D and decreasing τ we can increase CpssAv. It should be
between MEC (minimum effective concentration) and MSC (maximum safe
concentration).

Unit 6: Non Linear Pharmacokinetics or Dose Dependent
Pharmacokinetics or Mixed Order Pharmacokinetics or Capacity Limited
Pharmacokinetics or Saturation Pharmacokinetics
6.1: Introduction:
1. If the rate of ADME of a drug follows first order kinetics at low dose and zero
order at high dose, the ADME of drug is following mixed order
pharmacokinetics.
2. Example: Riboflavin is absorbed by carriers in GIT. At low doses, absorption
follows first order kinetics. At high doses, carriers become saturated and
absorption follows zero order kinetics. Hence, riboflavin absorption is
following mixed order kinetics.
6.2: Evidence for non linear pharmacokinetics:

1. In linear pharmacokinetics, the various pharmacokinetic parameters like F,
Ka, Ke, t1/2, Cl, are constant. In nonlinear pharmacokinetics, these
pharmacokinetic parameters change with the dose given to the patient.
2. In linear kinetics, if dose is doubled, AUC will be doubled. If dose is
increased by three times AUC will increase by three times. In case of
nonlinear kinetics the AUC will not change in a direct proportional manner.
3. In linear kinetics, if dose is doubled, Css will be doubled. If dose is increased
by three times, Css will increase by three times. In case of nonlinear kinetics,
the Css will not change in a direct proportional manner. Example: when the
dose of phenytoin is increased from300 mg/day to 450 mg/day, the
Cssincreased by 10 times.
6.3: Causes for Non Linear Pharmacokinetics:

Nonlinear drug absorption: Riboflavin is absorbed by carriers in GIT. At low
doses, absorption follows first order kinetics. At high doses, carriers become
saturated and absorption follows zero order kinetics. Hence riboflavin
absorption is following mixed order kinetics.
Non linear drug metabolism: Some drugs are metabolized in liver by enzymes.
At low doses, metabolism follows first order kinetics. At high doses, enzymes
become saturated and metabolism follows zero order kinetics. Hence liver

metabolism is following mixed order kinetics. Example: Phenytoin, alcohol
shows mixed order metabolism.
Example: An epileptic patient took 300 mg / day phenytoin for two weeks, his
plasma concentration was found to be 4 mg/L. Dose was increased to
500 mg / day, after 20 days Cp was found to be 36 mg/L, it increased by nine
times, because enzymes that were metabolizing phenytoin were saturated and
phenytoin plasma concentration increased greatly producing side effects.
Non linear drug distribution: Some drugs bind to proteins in blood. At low
doses, protein binding follows first order kinetics. At high doses, proteins are
saturated with drug and protein binding follows zero order kinetics. As a result,
free drug concentration increases greatly and high amount of free drug is
available for distribution. This may even cause toxic effects. Example:
salicylate, phenylbutazone, saturate albumin in blood.
Non linear drug elimination: Drugs that undergo tubular secretion and
reabsorption by carriers in kidney show non linear pharmacokinetics. At low
doses, tubular secretion and reabsorption follows first order kinetics. At high
doses, carriers become saturated and tubular secretion and re absorption
follows zero order kinetics. Hence elimination is following mixed order kinetics.
Example: Penicillin G is eliminated by tubular secretion and its elimination
follows non linear kinetics.
6.4: Non Linear Pharmacokinetics Equation / Michaelis-Menten Equation:

Michaelis - Menten Equation is used to calculate pharmacokinetic parameters
in mixed order kinetics.
Michaelis - Menten Equation is used to
calculate pharmacokinetic parameters in
mixed order kinetics.
Vmax = Maximum speed possible with the

process. C = Concentration of drug,
Km = Michaelis constant which depends on
interaction between drug and carrier or
enzyme.
Three situations can be considered, depending on values of Km and C.

a. When Km = C, then Speed = Vmax / 2.
b. When Km is very large than C, then, Speed = VmaxC/Km.The process is
following first order kinetics.
c. When Km is very small than C, then, speed = Vmax.The process speed is
constant, i.e. the process is following zero order kinetics.
The other pharmacokinetic parameters can be calculated using the below

equations.
CLT = Total Clearance, D = dose,
t1/2 = Biological half life,
F= bio availability, τ = dosing interval

Unit 7: Non Compartmental Pharmacokinetics
7.1 Introduction:
1. It is also called model independent method.
2. Calculation of pharmacokinetic parameters is difficult in compartment
models.
3. Hence non compartmental pharmacokinetics is used to calculate
pharmacokinetic parameters.
4. It is based on statistical moment theory. After an IV administration the
drug molecules are randomly distributed in the body. Some molecules are
eliminated quickly while some drug molecules are eliminated slowly. The
difference in the residence time for each molecule depends on chance
(probability) according to statistical moment theory.
5. From this theory, the mean residence time (MRT)of the drug in the body can be
found out.
7.2 Determination of Pharmacokinetic Parameters, MRT – IV
administration:
1. Give an IV dose to a person and collect his blood samples at different time
intervals.
2. Analyze the blood samples and construct a Cp versus time graph. This
curve is called zero moment curve.
3. Now construct a Cpt versus time graph. This is called first moment curve.
4. Calculate the area under the zero moment curve (AUC) and first moment
curve (AUMC) by trapezoidal rule.
5. The average time that the drug resides (stays) in the body is given by mean
residence time (MRT).
6. MRT = Total residence time for all drug molecules / Number of drug
molecules
7. MRT = AUMC / AUC
8. MRT represents the time taken for 63.2 % of drug to be eliminated from the
body.
9. If MRT is more, the drug is eliminated slowly from the body.
If MRT is less, the drug is eliminated quickly from the body.

Zero Moment Curve First Moment Curve
300 1000
250 800
200
600
Cp . t
Cp
150
400
100
50 200
0 0
0 5 10 15 20 25 30 0 5 10 15 20 25 30
Time Time
7.3 Determination of Pharmacokinetic Parameters MRT – Extra Vascular administration:

1. In IV administration, the MRT of a drug is generally constant.
2. In oral administration the drug spends additional time at the site of
administration. Mean absorption time MAT is the average time a drug
molecule spends at absorption site.
3. Give an oral dose to a person and collect his blood samples at different
time intervals. Analyze the blood samples and construct zero moment and
first moment curves.
4. MRToral = AUMC / AUC
5. MRToral= MRTiv + MAT
6. MAT can be found out if we know MRToral and MRTiv.
7. MAT of different brands of same drug can be compared for absorption
studies.
Example: MRT of paracetamol IV injection is 5 hours, MRToral of crocin is 6
hours and MRToral of calpol is 7 hours. So MAT of crocin is 1 hour and calpol is
2 hours.
It indicates that crocin is getting absorbed faster than calpol.
Zero Moment Curve First Moment Curve
140
900
120
800
100 700
80 600
Cp
Cp . t
60 500
400
40
300
20 200
0 100
0 5 10 15 20 25 30 0
0 5 10 15 20 25 30
Time
Time

7.4: Advantages of Non Compartmental Analysis:
1. Calculation of pharmacokinetic parameters is difficult in compartment
models. This model is simple for calculating pharmacokinetic parameters.
2. No assumption of compartment model is required.
Disadvantages:
1. It does not treat non - linear cases satisfactorily.

Unit 8: Bioavailability and Bioequivalence
8.1: Definitions:
1. Bioavailability: The rate and extent (amount) of drug reaching the blood
from the dosage form is called bioavailability. Example: Bioavailability of an
IV injection is 100 %. Bioavailability of a tablet is 80 %.
2. Absolute bioavailability: If the bioavailability of a product is compared
with an IV injection, it is called absolute bioavailability. Example:
Bioavailability of diclofenac tablets is compared with diclofenac injection.
3. Relative bioavailability: If the bioavailability of a product is compared
with an oral solution, it is called relative bioavailability. Example:
Bioavailability of paracetamol tablets is compared with paracetamol elixir.
4. Bioequivalent products: If the bioavailability is nearly same for the two
products, they are called bioequivalent products. Example: Crocin and
calpol tablets have 500 mg paracetamol and are bioequivalent.
5. Pharmaceutical equivalents are drug products that contain the same drug
and are of the same dosage form. They are identical in strength,
concentration, and route of administration. Additives may vary.
Example: Calpol and Crocin tablets have 500 mg paracetamol.
6. Pharmaceutical alternatives are drug products that contain the same drug
but are different salts, esters, or complexes. Example: Tetracycline
hydrochloride and tetracycline phosphate capsules.
7. Generic product: It is an alternative to innovator product. It will show
the same therapeutic performance as the innovator product. Example: Bayer
company is innovator of ciprofloxacin.
8.2: Objectives of bio availability studies:
1. Development of a suitable dosage form for the newly discovered drug.
Example: If a drug is having poor absorption in GIT, it is formulated as an
injection.
2. To study the effect of additives on bioavailability of drugs.
3. To study the effect of food and patient related factors on bioavailability of
drugs.
4. Quality control of drug products during manufacturing.
5. Comparison of bioavailability of generic product with innovator product.

8.3: Methods for assessing bioavailability:
1. Pharmacokinetic methods using blood level data or urinary excretion data of
drugs.
2. Pharmacodynamic methods based on pharmacological or therapeutic
response.
3. Pharmacokinetic method using blood level data:
a. A human volunteer is given an IV dose and blood samples are collected at
different time intervals.
b. After suitable wash out period, the human volunteer is given a tablet orally
and his blood samples are collected at different time intervals.
c. Now graphs are constructed by taking time on x axis and plasma
concentration of drug on y axis.
d. The bioavailability of the product is found out from the graphs using the
below formula.
e. Bioavailability = F = AUC of oral product x IV dose/AUC of IV product x Oral dose.
Blood level curve for IV injection Blood level curve for oral tablet
4. Pharmacokinetic method using urine data:

5. The principle in this method is, the urinary excretion rate of drug is
directly proportional to plasma concentration of drug.
6. The human volunteer is asked to fast overnight. Water loading is done by
taking 400 ml of water after fasting.
7. After one hour from water loading, the urine bladder is emptied completely,
and this urine sample is used as blank.
8. Now the IV product is administered. 200 ml water must be taken orally
every one hour for four hours.
9. Urine samples are collected at different time intervals. Each time, the total
volume of urine should be measured accurately.
10. Urine samples should be collected for at least seven biological half-lives.

11. The urine samples are analyzed for drug content. Then, the total amount
of drug excreted in urine at each time interval is calculated.
12. Rate of urinary excretion of drug is calculated for each time interval.
13. Now a graph is plotted by taking time on X axis and rate of urinary
excretion of drug on Y axis.
14. After suitable wash out period, the human subject is given a tablet orally
and his urine samples are collectedat different time intervals. Rate of
urinary excretion of drug versus time graph is constructed.
15. The bioavailability of the product is found out from the graphs.
16. Bioavailability = F= AUC of oral product x IV dose/AUC of IV product x Oral dose.
IV administration Oral administration

Acute pharmacological response method:
a. In this method, the product is given by IV / oral route and the

pharmacological response is measured.
b. Example: ECG readings, B.P, pupil diameter etc. are measured at different
time intervals.
c. Then curves are constructed, by taking time on x axis and the
pharmacological effect on y axis.
d. Pharmacological response should be measured for at least three biological
half-lives.
e. By comparing the AUC for IV product and oral product, bioavailability can
be calculated.
6. In Vitro drug dissolution rate and bioavailability:
a. Dissolution rate testing is a simple method to have an idea about
in vivo bioavailability.
b. The dissolution test mimics the in vivo conditions.

c. The dissolution test is carried on the two brands of products and their
graphs are compared. Time is taken on x axis and % of drug dissolved is
taken on y axis. Then, the t50, t90 and AUC are calculated and compared
for the two brands.
d. The difference factor f1 and similarity factor f2 are calculated.
e. If f1 is zero and f2 is 100 both the products will have same bioavailability.
f. If difference factor is greater than 15 and similarity factor is less than 50,
the two products will have different bioavailability.
8.4: Experimental design in bioavailability / bioequivalent studies /

evaluation of bioavailability studies:
1. Bioequivalent studies are carried out with generic product and innovator
product.
2. These studies are carried out in healthy, young, adult, male volunteers.
3. Latin square cross over design is used for these studies.
4. This design has 12 volunteers. They are divided into two groups. First
group receives generic product and the second group receives innovator
product. Blood samples or urine samples are collected and analyzed for
drug.
5. After wash out period (one week),first group receives innovator and second
group receives generic product. Blood samples or urine samples are
collected and analyzed for drug.
6. Now graphs are constructed by taking time on X axis and Cp on y axis.
From the AUC values, the bioavailability of the product is calculated.
7. Statistics is applied to the results to know whether the generic and
innovator product are bioequivalent or not.
8. Randomized block design: In this design, the volunteers are divided into
homogenous blocks.
9. Example: We want to compare the bioavailability of six brands of
paracetamol tablets. We will take 60 volunteers and divide them into 10
blocks. Each block has six homogenous volunteers.
10. Now, each volunteer in a block will receive one brand randomly.
11. This is done for all the 10 blocks.
12. Blood samples are taken and analyzed for drug and graphs are
constructed.

13. Statistical analysis of the AUC, Cmax, tmax is done to know whether all
the six brands are bioequivalent or not.
8.5: In vitro and in vivo correlation methods:

1. There are various methods to correlate in vitro dissolution data and in vivo
data.
2. If there is a good correlation between in vitro and in vivo data, we can
predict in vivo performance from in vitro dissolution data.
3. There are three levels of correlation, level A, level B and level C.
4. Level A IVIVC: It is a point to point correlation between in vitro dissolution
rate and in vivo input rate. In vitro data can be used to predict in vivo
profile. (Cmax, Tmax, AUC and elimination half-life.)
5. Level B correlation: It is between mean dissolution time with mean residence
time of the drug.
6. A level C correlation is between a single in vitro dissolution parameter and a
single in vivo dissolution parameter. Example: Correlation between amount
of drug dissolved at 30 minutes and Cmax.

Problems in Biopharmaceutics and Pharmacokinetics
1. A tablet containing 500 mg drug was taken orally, it took 20 minutes
for absorption. Calculate the speed of absorption. (Ans: 25 mg/min)
2. A tablet containing 200 mg drug was taken orally, it took 10 minutes
for absorption. Calculate the rate of absorption. (Ans: 20 mg/min)
3. 100 mg of drug was given by I.V route. It took 25 hours for complete
elimination of the drug. Find the rate of elimination. (Ans: 4 mg/hr)
4. 200 mg of drug was given by I.V route. It took 10 hours for complete
elimination of the drug. Find the rate of elimination. (Ans: 20 mg/hr)
5. A tablet containing 500 mg drug was taken orally. Only 400 mg drug
was absorbed in 40 minutes, the rest was excreted along with fecal
matter, find out the rate and extent of absorption or % bioavailability.
(Ans: Rate= 10 mg/hr, % Bioavailability = F = 80 %)
6. A tablet containing 300 mg drug was taken orally. Only 270 mg drug
was absorbed in 54 minutes, the rest was excreted along with fecal
matter, find out the rate and extent of absorption or % bioavailability.
(Ans: Rate= 5 mg/min, % Bioavailability = F = 90 %)
7. 100 mg of drug was given by IV route. After 6 hours the drug remaining
in the body is 40 mg. Calculate the zero order rate constant for
elimination of the drug. (Hint: Ct = Co – Kot), (Ans: Ko = 10 mg/hr).
8. 200 mg of drug was given by IV route. After 6 hours the drug remaining
in the body is 80 mg. Calculate the zero order rate constant for
elimination of the drug. (Hint: Ct = Co – Kot), (Ans: Ko = 20 mg/hr).
9. 60 mg of drug was given by IV route. The zero order elimination rate
constant is 5 mg/hr, calculate the amount of drug in the body after 6
hours. (Hint: Ct = Co – Kot), (Ans: 30 mg).
10. Calculate the elimination half life for the drug in the above problem.
(Ans: 5 hours)
11. 100 mg of drug was given by IV route. The zero order elimination
rate constant is 5 mg/hr, calculate the amount of drug in the body
after 8 hours. (Hint: Ct = Co – Kot), (Ans: 60 mg).
(Ans: 10 hours)
13. 100 mg of drug was given by IV route. After 1 hour the drug
remaining in the body is 90 mg. Calculate the first order rate constant

for elimination of the drug. (Hint: Log Ct = Log Co – K1t / 2.303),
(Ans: K1 = 0.1/hr).
(Ans: 6.93 hours)
15. 400 mg of drug was given by IV route. After 1 hour the drug
remaining in the body is 320 mg. Calculate the first order rate constant
for elimination of the drug. (Hint: Log Ct = Log Co – K1t / 2.303),
(Ans: K1 = 0.2/hr).
(Ans: 3.465 hours)
17. After an IV injection of 600 mg drug, blood samples were collected
at different time intervals and were analyzed for drug concentration.
The results are given in the below table. By graphical method,
determine the order of elimination and calculate all the possible
S.NO Time, hours Cp, mg/L

1 2 98
2 4 96
3 6 94
4 12 88
5 24 76
6 48 52
7 96 4
(Ans: Zero order elimination, Co = 100 mg/L, Ko = 1 mg/L/hr,

t1/2 = 50 hours, Vd = 6 L, AUC = 100 hr x mg/L)

S.NO Time, hours Cp, mg/L
1 1 40
2 2 30
3 3 20
4 4 10
5 5 0
(Ans: Zero order elimination, Co = 50 mg/L, Ko = 10 mg/L/hr,

t1/2 = 2.5 hours, Vd = 10 L, AUC = 5 hr x mg/L)

S.NO Time, Concentration of Log (Concentration of drug in
hours drug in blood, mg/L blood, mg/L)
1 2 90
2 4 81
3 6 73
4 8 66
5 10 60.5
6 12 54
(Ans: First order elimination, Co = 100 mg/L, K1 = 0.05 /hr,

t1/2 = 13.86 hours, Vd = 5 L, AUC = 2000 hr x mg/L)

S.NO Time, Concentration of Log (Concentration of drug in
hours drug in blood, mg/L blood, mg/L)
1 2 100
2 4 50
3 6 25
4 8 12.5
5 10 6.25
6 12 3.125
(Ans: First order elimination, Co = 200 mg/L, K1 = 0.3465 /hr,

t1/2 = 2 hours, Vd = 5 L, AUC = 578 hr x mg/L)
21. In IV infusion, the rate of drug administration is 1 mg/min, Vd of
drug is 10 L, Ke = 0.01 /min, calculate the plasma concentration at
every 60 minute intervals for 12 hours. Draw a graph of Cp vs time.
22. In IV infusion, the rate of drug administration is 2 mg/min, Vd of
drug is 10 L, Ke = 0.01 /min, calculate the plasma concentration at
every 60 minute intervals for 12 hours. Draw a graph of Cp vs time.
23. A 500 mg tablet was taken orally. The bioavailability factor is 1, Ka
and Ke are 0.3 and 0.1/ hr respectively. Vd is 10 L. Calculate the
plasma concentration of drug at 2, 4, 6, 8, 10, 12, 16, 20, 24, 36 and
48 hours. Use the below equation to calculate Cp at different time
intervals.
Use the data to draw a graph in method of residuals and calculate the Ka.

24. Dose of a drug is 200 mg. It is given every 8 hours. The Vd is 10 L.
The elimination rate constant of the drug is 0.1 / hr. Calculate Cssmax
and Cssmin. Use the below equation. (e= 2.718)
25. Dose of a drug is 100 mg. It is given every 6 hours. The Vd is 10 L.

The elimination rate constant of the drug is 0.1 / hr. Calculate Cssmax
and Cssmin. Use the below equation. (e= 2.718)
26. A patient received 250 mg of an antibiotic by IV injection.
Concentration of drug in blood at different time intervals is given in
below table. After wash out period, he was give a 500 mg capsule of the
same antibiotic orally. The concentration of drug in blood at different
time intervals is also given in below table. Draw graphs and calculate
the bioavailability of the capsule. Calculate the bioavailability of the
capsule.
Time, Conc. Of drug in blood Conc. Of drug in blood with 500 mg
hr with IV 250 mg, capsule
mg/L mg/L
1 6.3 3.1
2 5 4.7
3 4 5.2
4 3.2 5.3
6 2 4.5
8 1.3 3.4
12 0.5 1.7
(Hint: Draw Cp vs time graph, calculate AUC by trapezoidal rule and

then calculate AUC, Ans = 0.73 or 73 %)

27. A drug is following non linear absorption. The below table gives the
dose of drug and speed of absorption. Draw a graph using the below
data and find out Vmax and Km. (Ans: Vmax = 5 mg/min, Km = 25 mg)
S.NO Dose, mg Speed of absorption, mg/min
1 10 1
2 20 2
3 30 3
4 40 4
5 50 5
6 60 5
7 70 5
8 80 5
28. 50 mg drug is given by IV route. The below table gives the plasma
concentration at different time intervals. The terminal elimination rate
constant of drug is 0.1 / hr. Draw the zero moment curve and first
moment curve and calculate MRT. (Ans: MRT = 9.74 hrs.)
S.NO Time Cp, mcg/L
1 0 250
2 1 225
3 3 185
4 6 135
5 9 105
6 12 77
7 18 40
8 24 22

29. 500 mg drug is given by oral route. The below table gives the plasma
concentration at different time intervals. The terminal elimination rate
constant of drug is 0.1 / hr. Draw the zero moment curve and first
moment curve and calculate MRT.
S.NO Time Cp, mcg/L
1 0 0
2 1 50
3 3 100
4 6 200
5 9 200
6 12 100
7 18 50
8 24 0

Model Questions
Unit 1: Introduction to Biopharmaceutics
1. Define Biopharmaceutics and Pharmacokinetics. 2M
2. What is the use of studying biopharmaceutics? 2M
3. What is the use of studying pharmacokinetics? 2M
4. Explain the structure of cell membrane with a neat diagram. 5M
5. Define absorption, distribution, metabolism and excretion of drugs. 2M
6. Explain the different mechanisms of drug absorption with a neat
labelled diagram. 10 M
7. Explain the factors affecting passive absorption of drugs using the
Fick’s law of diffusion equation. 5M
8. What is the difference between passive transport and active transport
of drugs? 2M
9. List out the various mechanisms of drug absorption. 2M
10. Explain the biological factors affecting drug absorption. 10M
11. Explain pH partition theory in relation to absorption of drugs. 5M
12. Why is absorption of drugs more in small intestine than in the
stomach? 2M
13. Explain the physico - chemical factors of drug affecting drug
absorption. 10M
14. Explain the dosage form factors affecting drug absorption. 5M
15. Explain first pass effect and its significance. 2M
16. Explain about rate limiting steps in drug absorption. 5M
17. Give the BCS classification of drugs. 5M
18. Explain the dissolution testing of tablets with neat diagrams. 5M
Unit 1B: Distribution of drugs

1. Explain the concept of distribution with a diagram. Why is it a
reversible process? 5M
2. Explain the blood brain barrier with a neat labelled diagram. 5M
3. Explain the various factors affecting distribution of drugs. 10M
4. Define volume of distribution, give its significance. 2M.
5. Explain protein binding of drugs and give its importance. 5M
6. Explain the various factors affecting protein binding of drugs. 10M
7. How does protein binding affect volume of distribution of drugs? 2M

8. Explain tissue binding of drugs with examples. 5M
Unit 1C: Metabolism and excretion of drugs

1. Explain metabolism of drugs with examples? 5M
2. Explain phase I reactions with examples. 10M
3. Explain phase II reactions with examples. 10M
4. Explain the various factors affecting metabolism of drugs. 10M
5. Explain renal excretion of drugs with a neat labelled diagram of
nephron? 10M
6. Explain the various factors affecting renal excretion of drugs. 10M
7. Write short notes on renal clearance and its importance. 5M
8. Explain biliary excretion and biliary recycling of drugs with a neat
labelled diagram. 5M
9. Explain the various factors affecting biliary excretion of drugs. 10M
10. Explain salivary excretion and salivary recycling of drugs with a neat
labelled diagram. 5M
Unit 2: Introduction to Pharmacokinetics

1. What is the difference between zero order and first order kinetics? 2M
2. Define pharmacokinetics and give its importance. 2M
3. Explain the different types of compartment model with diagrams. 5M
4. Write short notes on blood level curves. 5M
Unit 3: One compartment open model

1. Explain the pharmacokinetics of a drug following one compartment
model – IV Bolus injection. Give the necessary equations and graphs to
calculate the pharmacokinetic parameters of the drug. 10M
model – IV infusion. Give the necessary equations and graphs to
model – extra vascular administration. Give the necessary equations
and graphs to calculate the pharmacokinetic parameters of the drug.
10M

4. Explain method of residuals to calculate the absorption rate constant
of a drug. 5M
5. Explain Wagner Nelson method to calculate the absorption rate
constant of a drug. 5M
Unit 4: Multi Compartment model
1. Explain the pharmacokinetics of a drug following two compartment

model – IV Bolus injection. Give the necessary equations and graphs to
model – IV infusion. Give the necessary equations and graphs to
model – extra vascular administration. Give the necessary equations
and graphs to calculate the pharmacokinetic parameters of the drug.
10M
Unit 5: Multiple – Dosage Regimens
1. Discuss the kinetics of a drug in multiple dosage regimen. Explain

with necessary equations and graphs. 10 M.
2. Explain the terms Cssmax and Cssmin. 2M.
3. Explain the terms dosing interval and loading dose. 2M
4. What is the need for a loading dose in IV multiple dosage regimen. 2M
Unit 6: Non Linear Pharmacokinetics
1. What is the difference between zero order and first order kinetics?
2. What is the difference between linear and non linear kinetics?
3. With an example, explain non linear kinetics in drug absorption. 2M
4. With an example, explain non linear kinetics in protein binding. 2M
5. With an example, explain non linear kinetics in drug metabolism. 2M
6. With an example, explain non linear kinetics in drug elimination. 2M
7. What is the evidence that the drug is following non linear

pharmacokinetics? 2M
8. Discuss about Michaleis Menton equation in describing non linear
pharmacokinetics. 5M
Unit 7: Non Compartmental Pharmacokinetics

1. What is the difference between compartmental and
non compartmental analysis? 2M
2. Explain the principle behind non compartmental analysis. 2M
3. Explain the difference between MAT and MRT. 2M
4. How do you determine pharmacokinetic parameters in IV
administration by non compartmental analysis? 5M
5. How do you determine pharmacokinetic parameters in extra vascular
administration by non compartmental analysis? 5M
Unit 8: Bioavailability and Bioequivalence
1. Define bioavailability, absolute bioavailability and relative

bioavailability. 2M
2. What is the difference between bioequivalent products and
pharmaceutical equivalents? 2M
3. Define pharmaceutical alternatives and generic product. 2M
4. What is the need for bioavailability studies?
5. Discuss any one method for assessing the bioavailability of a
product.
6. How will you determine the bioavailability of a product by urinary
excretion method? 5M
7. Discuss about acute pharmacological response method to assess the
bioavailability of a drug product. 5M
8. How do you assess the bioavailability of a drug product by
dissolution testing?
9. Discuss about experimental designs in carrying out bioavailability
experiments. 10M
10. Explain latin square design. 5M
11. Explain randamoized block design of experiments. 5M
12. Write short notes on IVIVC. 5M

Biopharmaceutics and Pharmacokinetics

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Biopharmaceutics and Pharmacokinetics

(As per PCI Syllabus, for IV Pharm. D students)

1. First understand the topic / concept.

6. Revise after another week. It will take now 1 hour.

9. So, u should not postpone learning. Learn the chapter, as soon as it

10. In case of chemistry, maths, etc. you have to practice the

If u start your day by reading the below positive auto suggestions,

By reading these auto suggestions daily once in the morning and

1. I am an honest, cool, calm and relaxed person.

4. I will not run away from problems, I will solve them.

5. I am always with good and positive people.

6. I will always practice healthy habits.

7. I respect myself and others.

8. I always wish good for others.

9. I love my job and will work hard with dedication.

10. I will never postpone things.

11. I always do right things.

13. I practice self-discipline and always finish what I start.

14. I take full responsibility for my thoughts and actions.

15. I am a courageous person.

16. I will improve daily.

18. I am happy with what I have.

19. I will always discuss, instead of arguing. (Argument is to find out

20. I will walk daily for one hour.

21. I will take only healthy food.

22. I will meditate daily for 30 minutes.

23. I will always teach moral values to children.

24. I am healthy and always energetic.

For further details on positive thinking, please read the book,

1. Biopharmaceutics: Introduction to Biopharmaceutics a. Absorption of drugs

2. Pharmacokinetics: Introduction to Pharmacokinetics. a. Mathematical

3. One compartment open model: a. Intravenous Injection (Bolus)

4. Multi compartment models. a. Two compartment open model. b. IV bolus, IV

5. Multiple – Dosage Regimens. a. Repetitive Intravenous injections – One

6. Nonlinear Pharmacokinetics. a. Introduction b. Factors causing Non-

7. Non compartmental Pharmacokinetics. a. Statistical Moment Theory.

8. Bioavailability and Bioequivalence. a. Introduction. b. Bioavailability study

a. Biopharmaceutics and Clinical Pharmacokinetics by, Milo Gibaldi

b. Remington’s Pharmaceutical Sciences, By Mack Publishing Company, Pennsylvnia.

c. Pharmacokinetics: By Milo Glbaldi Donald, R. Mercel Dekker Inc.

d. Hand Book of Clinical Pharmacokinetics, By Milo Gibaldi and Laurie Prescott.

e. Biopharmaceutics and Pharmacokinetics; By Robert F Notari

Sir C. R. Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India 1

Unit 1 (a): Absorption of drugs from Gastro Intestinal Tract (GIT)

1.3 Structure of cell membrane and its significance (importance) in drug

Sir C. R. Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India 2

1.4 Mechanisms of drug absorption: The different mechanisms of drug

a. Passive diffusion: 90 % of the drugs are absorbed by this mechanism. In

Km/w = membrane water partition coefficient of drug

Sir C. R. Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India 3

Sir C. R. Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India 4

6. pH of the stomach is around 1 to 3, weakly acidic drugs are un ionized

Sir C. R. Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India 5

Sir C. R. Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India 6

1.7 Pharmaceutical factors / Dosage form factors / Formulation factors

Sir C. R. Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India 7

1.8: First pass effect and its significance:

1.9: Rate limiting steps in drug absorption:

Sir C. R. Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India 8

Sir C. R. Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India 9

Apparatus 1: Basket type Apparatus II: paddle type

Sir C. R. Reddy College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India 10

2. Distribution of drug from blood to tissues is a reversible process.

1.13: Physiological Barriers for Drug Distribution: