1.
PHARMACOKINETICS
Prof. Amol B. Deore
Department of Pharmacology
MVP’s Institute of Pharmaceutical Sciences, Nashik

2.
Introduction
• Pharmacokinetics is study of the movement of drug molecules in body.
• It includes absorption, distribution, metabolism and excretion of drug.
Absorption
Distribution
Metabolism
Excretion

3.
Pharmacokinetics is the study of what happens to
drugs once they enter the body (the movement of
the drugs into, within and out of the body).
For a drug to produce its specific response, it
should be present in adequate concentrations at
the site of action.
This depends on various factors apart from the
dose.

4.
Absorption: First,
absorption from the
site of administration
permits entry of the
drug (either directly
or indirectly) into
plasma.
Distribution: Second,
the drug may then
reversibly leave the
bloodstream and
distribute into the
interstitial and
intracellular fluids.
Metabolism: Third,
the drug may be
biotransformed by
metabolism by the
liver or other tissues.
Elimination: Finally,
the drug and its
metabolites are
eliminated from the
body in urine, bile, or
feces.
In short, pharmacokinetics means what body does to the drug.

5.
Schematic Relationship Between
Pharmacokinetics and Pharmacodynamics

6.
DRUG
ABSORPTION

7.
Absorption is the passage
of the drug molecules
from the site of
administration into the
bloodstream.
absorption is the entry of
drug molecules into blood
capillaries via mucous
membrane of digestive
organs, or respiratory tract
or from site of injection.
In many cases, a drug must
be transported across one
or more biologic
membranes to reach the
bloodstream.

8.
The rate and extent of absorption
depend on the pH environment
where the drug is absorbed,
chemical characteristics of the drug,
and the route of administration.
If a drug is administered by oral
route, it has to cross the membranes
of GIT and blood vessels to enter
into the blood.

9.
Direct parenteral injection of drugs
(into systemic circulation,
cerebrospinal fluid, or tissue) avoids
first-pass metabolism and provides
rapid delivery to the site of action.
When drug is given intravenously, it
enters directly in to blood.

10.
On oral administration three processes precede drug absorption
Administration of
oral dosage form
Disintegration to
form granules
Deaggregation to
form fine particles
Dissolution to
form solution
Drug
Absorption

11.
Drug absorption in the stomach

12.
Cell membrane
• The cell membrane or biological membrane is made up of two layers of phospholipids
with protein molecules (Fig.1.6.3).
• All lipid soluble substances get dissolved in the cell membrane and readily permeate
into the cells.

13.
• The junctions between adjacent epithelial or endothelial cells have
pores through which small water-soluble molecules can pass.
• Movement of some specific substances is regulated by special carrier
proteins.
• The passage of drugs across biological membranes involves processes
like passive (filtration, diffusion) and active transport.

14.
MECHANISMS OF ABSORPTION OF DRUGS

15.
Water soluble (lipid
insoluble) that
always get ionised,
and hence, are
nondiffusible.
Lipid soluble that
remain unionise,
and hence, are
easily diffusible.
Those that are
partly ionised and
partly unionised
and hence partly
water soluble and
partly lipid soluble.
Weakly acidic
drugs remain
unionised at acidic
pH; whereas
weakly basic drugs
remain unionised
at alkaline pH.

16.
Cellmembrane
Outside (extracellular fluid) Inside (Intracellular fluid)
Ionized drug molecule Unionized drug molecule
Drug absorption

17.
Weakly acidic
drug
In acidic
medium
Remain
unionized
Readily
absorbed
Weakly acidic
drug
In alkaline
medium
ionized Slowly
absorbed

18.
Weakly basic drug
In alkaline
medium
Remain unionized Readily
absorbed
Weakly basic
drug
In acidic medium ionized Slowly
absorbed

19.
Passive diffusion
Simple or passive diffusion is the
most common process by which a
drug gets absorbed and distributed
in the tissues.
In this process, the drug molecules
move across the cell membrane, in
proportion to their concentration,
from higher to lower
concentration.

20.
Cellular energy is not
required and the system
does not become
saturated.
Water-soluble drugs
(ionized) penetrate the cell
membrane through
aqueous channels or pores,
lipid-soluble (unionized)
drugs readily move across
most biologic membranes
due to their solubility in the
membrane lipid bilayers.

21.
Passive Diffusion

22.
Facilitated diffusion
Certain agents can enter the cell through membrane transporter proteins
that facilitate the passage of large molecules.
These transporter proteins undergo conformational changes, allowing the
passage of drugs or endogenous molecules into the interior of cells and
moving them from an area of high concentration to an area of low
concentration.

23.
C E L L M E M B R A N E
extracellular fluid with high
drug concentration
Intracellular fluid with low
drug concentration
Facilitated diffusion
Carrier transporter
proteins

24.
This process is known as
facilitated diffusion. It does not
required energy. It depends on
number of carrier proteins.
e.g., absorption of glucose, iron
and amino acids from intestine.

25.
Active transport
Active transport is an
energy-dependent process
that can move drugs using
protein-mediated transport
systems against a
concentration gradient.
It is capable of moving drugs
against a concentration
gradient, from a region of
low drug concentration to
one of higher drug
concentration.
The compound binds to a
specific carrier on one side
of the membrane and
moves across the cell.

26.
C E L L M E M B R A N E
extracellular fluid with low
drug concentration
Intracellular fluid with high
drug concentration
Facilitated diffusion
Carrier transporter
proteins
Energy Energy

27.
At the other side of the cell,
the complex dissociates and
the carrier moves back to
transport another molecule.
e.g., methyl DOPA,
levodopa, 5-fluorouracil.

28.
Endocytosis
This type of absorption is used to transport drugs of
exceptionally large size across the cell membrane.
Endocytosis involves engulfment of a drug by the cell
membrane and transport into the cell by pinching off
the drug filled vesicle.

29.
vitamin B12 is
transported across the
gut wall by
endocytosis.

30.
Factors Affecting Drug
Absorption
Several factors
influence the
rate and extent
of absorption
of a drug.

31.
Patient related factors
pH of GI fluid and the blood
Presence of food and other drug
in gastrointestinal tract
GI transit time
Surface area of gastrointestinal
organs
Disease state of gastrointestinal
organs
Gastrointestinal motility
First pass metabolism

32.
pH of GI fluid and the blood
Most of the drugs are either weak acids or week bases.
At the physiological pH of body fluids
(7.4), drug molecules exist as mixture of
ionized (charged electrolyte) and
unionized (free) molecular forms.
It is observed that, drugs which are
more lipid soluble remain as unionized
form; whereas water soluble drugs are
exist in ionized form.

33.
The principle is that: “The
cell membranes are more
permeable (absorptive) to
unionized form of a drug
than an ionized form.”
Weakly acidic drugs like
phenobarbitone and aspirin
would be in unionized form
at low pH of stomach, hence
these drugs are significantly
absorbed from stomach.
Weakly basic drugs like
amphetamine and morphine
would be in ionized form at
the low pH of stomach and
not well absorbed.

34.
As these drugs move down
in the intestine, the pH
increases and acidic drug
become more ionized,
whereas basic drugs are
less ionized.
Therefore absorption of
basic drugs increases as
the molecules move
through the intestine.

35.
Presence of food and other drug in GI tract
Most drugs are better absorbed in
empty stomach but they may cause
gastric irritation, nausea, vomiting,
gastric bleeding and ulcer.
Presence of food in the stomach
dilutes the drug and retards
absorption of drug. e.g., ampicillin,
roxithromycin, rifampicin, aspirin etc.

36.
The presence of other
drugs in gastrointestinal
tract may increase or
decrease the absorption of
drug due to drug-drug
interaction.
e.g., vitamin C enhances
the absorption of iron from
the gastrointestinal tract.
The calcium present in milk
and in antacids forms
insoluble complexes with
the tetracycline antibiotics
and reduces their
absorption.

37.
Surface area of GI organs
The greater the surface area
of the absorbing surface, the
faster is the rate of
absorption.
Drugs are better absorbed
from the small intestine than
the stomach due to greater
surface area.

38.
Disease states of GI organs
Absorption and first pass metabolism
may be affected in conditions
• Malabsorption, Thyrotoxicosis,
• Achlorhydria, Liver cirrhosis.

39.
Gastrointestinal motility
If gastric emptying is faster,
the passage of the drug to
the intestines is quicker
and hence absorption is
faster.
Increase in gastrointestinal
tract motility as in
diarrhoea, decreases
absorption of drugs due to
rapid elimination in faeces.
Vomiting also decreases
absorption of drugs.

40.
Drug related factors
Physical state of drug
Water or lipid solubility of
drug
Chemical stability
Molecular weight
Particle size of drug
Disintegration time and
dissolution rate
Drug formulation

41.
Physical state of drug
Drugs given in
liquid dosage
form are better
and rapidly
absorbed from
gastrointestinal
tract than when
given in solid
dosage forms.

42.
Solubility of drug
The biological cell membrane,
mucous membrane and blood
capillary endothelium are made
up of lipid bilayer.
The principle is that: “The cell
membranes are more
permeable to unionized form of
a drug than an ionized form.”

43.
If the drug is lipid soluble then its greater
fraction of drug molecules exist in
unionized form, hence the lipid soluble
drugs are absorbed better and greater
extent because cell membranes are more
permeable to unionized form of a drug.
If the drug is water soluble then its
greater fraction exists in ionized form.
Hence because of ionization water soluble
drugs poorly absorbed.

44.
Chemical stability
Chemically unstable drugs are
inactivated in gastrointestinal tract.
Penicillin-G is unstable in acid
medium (acid labile) of stomach and
cannot produce satisfactory results
on oral administration.
But penicillin-V is more stable in acid
medium of stomach (acid resistant)
than penicillin-G and therapeutically
effective.

45.
Molecular weight
Drugs with high
molecular
weight are not
usually
absorbed from
gastrointestinal
tract on oral
administration.
Such drugs may
be inactivated
by enzymatic
degradation.

46.
Particle size of drug
• The particle size of sparingly soluble drugs can affect their absorption.
• A tablet that contains large aggregates of the drug may not disintegrate
even on prolonged contact with gastric and intestinal juices and hence, may
be poorly absorbed.
• Small particle size is important for absorption of corticosteroids, antibiotics
like chloramphenicol and griseofulvin, certain oral anticoagulants and
spironolactone.
• On the other hand, for an anthelminthic such as bephenium
hydroxynaphthoate, the particle size should be large enough to reduce its
absorption.

47.
BIOAVAILABILITY
Bioavailability refers to the rate and extent of
absorption of a drug from a dosage form.

48.
the amount or percentage of an active drug that is absorbed
from a given dosage form, and reaches systemic circulation.
If 100 mg of a drug is administered orally and 70 mg is
absorbed unchanged, the bioavailability is 0.7 or 70%.
Determining bioavailability is important for calculating drug
dosages for nonintravenous routes of administration.
BIOAVAILABILITY

49.
Intravenous
administration leads to
100% of a drug
entering the body.
While by oral route bioavailability
may be low due to incomplete
absorption, plasma protein
binding and first pass metabolism
of the drug.

50.
100 mg drug
administered orally
70 mg drug absorbed in
bloodstream
Bioavailability is 0.7 or 70%

51.
Intravenous administration leads to 100% of a drug
entering the body. While by oral route
bioavailability may be low due to incomplete
absorption and first pass metabolism. On IM/SC
injection, drugs are almost completely absorbed.
e.g., bioavailability of chlortetracycline is 30%,
carbamazepine 70%, chloroquine 80%, minocycline
and diazepam 90%. Transdermal preparations are
absorbed systemically and may have 80-100%
bioavailability.

52.
analysis of plasma concentration of the drug at various time intervals after
its administration and plotting a serum concentration time curve.
The area under such a curve
(AUC) provides information
about the extent (amount of
drug absorbed) and the rate of
absorption

53.
Bioequivalence
Many different
pharmaceutical companies
can manufacture same
compound (with same dose
as well as dosage form)
e.g. phenytoin is available
as tab. Dilantin as well as
Tab. Eptoin.

54.
If the difference in the
bioavailability of these two
preparations (same drugs, same
dose, same dosage forms) is less
than 20%, these are known to be
bioequivalent.
As the term implies, these
are biologically equal i.e.
will produce similar plasma
concentrations.

55.
DRUG DISTRIBUTION
• Site of Action,
• Other Storage Sites In The Body,
• Organs of Metabolism
• Organs of Excretion.
Transports
of a drug
to

56.
Plasma proteins binding of drug
• Interstitial fluid,
• Intracellular fluid,
• Cerebrospinal fluid,
• Lymph,
• Endolymph,
• GI FLUID,
• Aqueous humour,
• Plasma
DRUG
DISTRIBUTION
IN BODY
FLUIDS

57.
•The plasma and other body fluids contain:
plasma proteins like albumin, globulin, glycoprotein, transferrin,
and lipoprotein (LDL, VLDL and HDL).
•Most of the drugs when enter in the body fluids bind to
proteins to form drug-protein complexes.
•Drug-protein binding is the reversible interaction of drugs
with proteins in plasma.

58.
• Drugs thus circulate in both free and bound forms and
there is a dynamic equilibrium between these two forms.
• Acidic drugs bind mainly to albumin,
• basic drugs frequently bind to other plasma proteins in
addition to albumin.
• Drug-protein binding depends on the affinity of the drug
for the protein
Drug + Protein Drug-Plasma Protein Complex + Unbound (Free) Drug

59.
Drug +
Plasma
Protein
Drug: Plasma
protein complex
unbound (free)
drug
Interaction with
specific receptor
Pharmacological
action
Site of
metabolism
Site of excretion
DRUG DEPOT

60.
Drug : Plasma Protein
complex
Drug Reservoir
No pharmacological
action
FREE DRUG MOLECULES PLASMA PROTEINS
Pharmacological action
Metabolism
Excretion

61.
Drug bound to proteins forms drug-protein complex.
This drug-protein complex is pharmacological inactive,
because it cannot cross cellular membrane to interact with its
site of action, hence acts as drug reservoir.
The free unbound form of the drug is pharmacologically
active and diffuses through blood capillary walls to reach the
site of action.

62.
As free drug molecules
undergo metabolism
and excretion, drug:
plasma protein
complex dissociates to
supply more free drug
molecules.
There are a large
number of drugs
which are more than
90% bound to plasma
albumin.
e.g., doxycycline,
warfarin,
indomethacin,
propranolol,
chlorpropamide,
imipramine and
phenytoin.

63.
Significance of plasma protein binding
The plasma
protein binding
of drug decides
it’s the duration
of action.
Greater the
plasma protein
binding prolong
will be the
action of drug.
Protein binding
delays the drug
excretion.

64.
BLOOD BRAIN BARRIER

65.
The Blood Brain Barrier (BBB) is semi-
permeable; that allows some materials
to cross, but prevents others from
crossing.
In the brain, the endothelium of blood
capillaries have tight junctions (no
intracellular pores or channels).
Moreover, glial cells envelop the
capillaries and together these form the
BBB.

66.
Only lipid soluble drugs are able
to penetrate BBB and produce
their action on central nervous
system such as levodopa,
diazepam, barbiturate, etc.
However, the water soluble and
ionized drug molecules can not
do not cross the BBB.

67.
DRUG METABOLISM
(BIOTRANSFORMATION)

68.
Drug metabolism is a process of chemical
modification of a drug and is carried out mostly by
enzymes.
Drugs treated by the body as foreign substances,
which body tries to remove from the body by
metabolism and excretion.
The sites for drug metabolism include liver,
kidney, gastrointestinal tract, lungs and plasma.

69.
The metabolism generally
results in the conversion
of a drug to a less active,
less lipid soluble, less
toxic metabolite and
hence easily excreted.
Active Drug Metabolism
less active
metabolite excretion

70.
Functionalization and
conjugation are chemical
reactions that produce more
water soluble metabolites.
The major enzyme associated
with drug metabolism in the
liver is the Cytochrome P450
family.
Microsomal enzymes: Present in
the smooth endoplasmic
reticulum of the liver, kidney and
GIT e.g., glucuronyl transferase,
dehydrogenase, hydroxylase and
cytochrome P450.
Non-microsomal enzymes:
Present in the cytoplasm,
mitochondria of different
organs. e.g., esterase, amidase,
hydrolase.

71.
Active drug Biotransformation
Less active
metabolite
Liver
Excretion
Drug Metabolism

72.
Types of biotransformation
Phase-I reactions: the drug is
converted to more polar
metabolite. If this metabolite is
sufficiently water soluble, then it
will be excreted in urine.
Phase-II reactions: Some
metabolites may not be
sufficiently polar to be excreted, it
undergoes metabolised phase–II
reactions.

73.
Phase-I reactions:
Oxidation (hydroxylation,
dealkylation, deamination,
dehalogenation, sulfoxide
formation), reduction and
hydrolysis.
Phase-II reactions:
Glucuronidation, conjugation,
acetylation, glycine
conjugation and methylation
reactions.

74.
Reactions Examples of drugs
Oxidation
Phenytoin, Diazepam, Ibuprofen,
Amphetamine, Chlorpromazine, Dapsone
Reduction Chloramphenicol, Halothane
Hydrolysis Pethidine, Procaine
Conjugation reactions
Glucuronide conjugation
Acetylation
Methylation
Glutathione conjugation
Chloramphenicol, Morphine
Sulfonamides, Isoniazid
Adrenaline, Histamine
Paracetamol

75.
First pass metabolism
Many drugs that are absorbed by the gastrointestinal
tract transported to the liver and undergo metabolism
before reaching the systemic circulation.
It is also called presystemic metabolism or first pass
effect and is an important feature of oral route of
administration.

76.
The reason is that all of the
venous blood from the
stomach, the small intestine,
and the large intestine enters
the portal vein and then
transported to the liver.
This reduces oral bioavailability.

77.
The extent of first pass metabolism differs from drug to drug and
among individuals from partial to total inactivation.
When it is partial, it can be compensated by giving higher dose
of the particular drug, e.g. nitroglycerine, propranolol,
metoprolol, imipramine, cimetidine, diazepam, salbutamol etc.
But for drugs that undergo complete first pass metabolism, the
route of administration has to be changed, e.g. isoprenaline,
hydrocortisone, insulin etc.

78.
DRUG EXCRETION
The excretion of drugs means the transportation of drug metabolites out of the body.
• Renal Excretion,
• Biliary Excretion
• Pulmonary Excretion.
The major
processes of
excretion
include
• Saliva,
• Sweat,
• Breast milk,
• Vaginal fluid, etc.
The minor
routes of drug
excretion are

79.
Renal excretion
The excretion of drug by the
kidney involves three stages-
Glomerular
filtration:
Tubular
reabsorption:
Tubular
secretion:

80.
Glomerular filtration
The rate of glomerular
filtration
Plasma protein binding,
Concentration of free drug in the
plasma
Molecular weight,
Glomerular filtration rate (GFR).

81.
• The ionized and free unbound form of drugs of low molecular weight
(<10,000) are easily filtered through the glomerular membrane.
• The glomerular filtration does not depend on the drug solubility hence
all hydrophilic or lipophilic drugs can cross the glomerular membrane.
• e.g., phenobarbitone, digoxin, ethambutol etc.

82.
Tubular reabsorption
• The tubular reabsorption depends on can occur in both the ways in
proximal and distal convoluted tubules.
• The unionized and lipophilic drug molecules are almost completely
reabsorbed from the glomerular filtrate into the blood stream by
passive diffusion.

83.
• The pH of the urine influences rate of passive diffusion and hence
excretion of certain weak acids and weak bases.
• Thus, weak acids are quickly eliminated in an alkaline urine, e.g.,
barbiturates and salicylates;
• while weak bases are rapidly excreted in an acidic urine, e.g.,
pethidine and amphetamine.

84.
Tubular secretion
• The tubular secretion can rapidly remove the plasma protein bound
drugs from the blood into tubular fluid because the protein bound
drugs have not been eliminated by glomerular filtration.
• For example:
• Acidic drugs include salicylates, chlorothiazide, probenecid, penicillin;
• Basic drugs include catecholamines, acetylcholine, histamine,
hexamethonium, morphine etc.

85.
Biliary excretion
• Certain drugs that are secreted by the
liver into the bile and then excreted
into the intestine where they may be
reabsorbed.
• In this way, the drugs will repeatedly
reabsorbed from the intestine and re-
excreted in the bile and thereby
prolongs the drug action so called as
‘enterohepatic circulation’.

86.
• The unabsorbed fraction of the orally administered drugs are eliminated
through the faeces.
• The high molecular weight, water-soluble metabolites and polar drugs are
undergo biliary excretion.
• e.g., chloramphenicol, tetracycline, oral contraceptives, erythromycin, aluminium
hydroxide, ferrous sulphate etc.

87.
Pulmonary excretion
The lungs are the main
route of elimination
for volatile lipophilic
substances such as
gases and volatile
liquids
• general anaesthetics,
paraldehyde and alcohol.
These volatile
substances that enter
the body through the
respiratory tract are
excreted by inhalation.
The excretion of these
drugs may be affected
in the presence of lung
disease conditions,
which may precipitate
the drug toxicity.

88.
Mammary excretion
The excretion of drugs into the
mother’s milk will depend
upon the bioavailability, lipid
solubility and the extent
active secretion of drugs in
milk.
As milk has lower pH (6.5), the
highly lipid soluble and basic
drugs are accumulated in the
milk.

89.
The drugs excreted in milk include
ampicillin, aspirin,
chlordiazepoxide, tetracycline,
diazepam, furosemide, morphine,
streptomycin etc.
So these drugs should be avoided
in breast feeding mothers as these
drugs have effects on infants.

90.
Saliva
Small amounts of
some drugs are
eliminated through
the saliva.
Excretion in saliva may
result in a unique
taste with some drugs
phenytoin,
clarithromycin; metallic
taste with metronidazole,
metoclopramide and
disulfiram.

91.
Skin
The certain drugs are excreted
through the sweat.
The compounds like lithium,
potassium iodide, rifampicin,
metalloids like arsenic and other
heavy metals like mercury are
present in sweat.

92.
Frequently asked questions in board exam
1) Define pharmacokinetics.
2) Enlist Factors affecting drug absorption. Explain any two.
3) Enlist processes of drug absorption. Explain any one.
4) Define with examples: Bioavailability
5) Explain: solubility of drug and local PH of GI organs.
6) Define drug distribution.
7) Explain Plasma protein binding of drug & its significance.
8) Define and explain drug metabolism (biotransformation).
9) Explain First pass metabolism.
10) Describe different channels (route) of drug excretion.

93.
Prof. Amol Deore