Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of drug into, through, and out of the body—the time course of its absorption, bioavailability, distribution, metabolism, and excretion.

1. Pharmacokinetics
Prof. Amol B Deore
MVP’s Institute of Pharmaceutical
Sciences, Nashik (INDIA)

2. OIn order to get its effect, a drug must be
administered in a suitable dosage form
at appropriate site.
OIt must be absorbed effectively from the
site of administration, and distributed in
the body to reach its site of action.
OAfter its action, for the termination of its
effect, the drug must be metabolized,
and its metabolites excreted from the
body.

3. Pharmacokinetics
O Pharmacokinetics is study of the movement of
drug molecules in body.
O It includes absorption, distribution, metabolism
and excretion of drug (ADME).
O In short, pharmacokinetics means what body does
to the drug.

4. Administration
Absorption
Distribution
Metabolism
Excretion
Removal

5. Drug absorption
O Absorption is movement of the drug from its site
of administration into the circulation. Simply
speaking, absorption is the entry of drug
molecules into blood via mucous membrane of
digestive organs, or respiratory tract or from site
of injection.
O When a drug is administered orally, it passes
through the mucus membrane of G.I.T. organs
and blood capillary membrane to enter in to the
blood circulation. When drug is given
intravenously, it enters directly in to blood.

6. Process of drug absorption on oral
administration
Oral preparation
Disintegration
Granules
Deaggregation
Fine particles
dissolution
Solution
Absorption

7. Cell membrane
O Biological cell membrane is a lipoprotein
membrane.
O The lipid portion of membrane is bilayer (double
layer) and made up of phospholipid and
cholesterol molecules.
O The proteins are located across the lipid bilayer.
The membrane contains many aqueous pores
(channels) though which filtration of small drug
molecules occur.

8. O structure of cell membrane

9. Drugs may cross body membranes
by following mechanisms
O Passive diffusion
O Filtration
O Active transport
O Facilitated diffusion
O Endocytosis

11. Passive diffusion
O The lipid soluble drug can cross the cell
membrane easily by diffusion. e.g. diazepam,
propranolol etc. the drug molecules cross the
cell membrane by dissolving in lipid bilayer of
membrane. The rate of drug transfer is directly
proportional to lipid/water coefficient. Greater
the coefficient of drug, faster the diffusion of the
drug through the membrane.

12. Filtration
O Filtration is passage of drugs through aqueous
pores in the membrane or through paracellular
spaces. This can be accelerated if hydrodynamic
flow of the solvent is occurring under hydrostatic
or osmotic pressure gradient, e.g. across most
capillaries including glomeruli. Lipid-insoluble
drugs cross biological membranes by filtration if
their molecular size is smaller than the diameter of
the pores.

13. Active transport
O It means the passage of drug across the
biological membrane against their
concentration gradient with the help of carriers
by the use of energy (ATP). e.g. methyl dopa,
levodopa, 5-fluoro-uracil. It involves movement
of drug molecules from lower to higher
concentration. It is carrier mediated i.e. carries
by a specific transport protein.

14. Facilitated diffusion
O It means the passage of drug across the
biological membrane along the concentration
gradient by the protein carrier mediated system
also called as carrier mediated diffusion. It
depends on number of carrier e.g. absorption
of glucose, iron and amino acids from intestine.

15. Endocytosis
O It is the process by which the large
molecules are engulfed by the cell
membrane and releases them
intracellularly e.g. protein, toxins

16. Factors affecting drug
absorption

17. A) Biological factors
1) Local PH of GIT organs
2) Presence of food and other drug in GIT
3) Surface area of GIT organs
4) Disease state of GIT organs
5) GIT motility
6) First pass metabolism
B) Pharmaceutical factors
1) Physical state of drug
2) Water or lipid solubility of drug
3) Chemical stability
4) Molecular weight
5) Particle size of drug
6) Disintegration time and dissolution rate
7) Enteric coating of drugs

18. Local PH of GIT organs
O Most of the drugs are weak acids or bases and
at the physiological pH of body fluids (7.4), drug
molecules exist as mixture of ionized (charged)
and unionized (free) molecular form.
O It is observed that, drugs which are more lipid
soluble exist as unionized form; whereas water
soluble drugs are exist in ionized form.
O The principle is that: “Cell membranes are
more permeable to unionized form of a drug
than to an ionized form.”

19. For examples:
O Acidic drugs like phenobarbitone and aspirin would
be in unionized form at low pH of stomach. Hence
these drugs are significantly absorbed from stomach.
O Basic drugs like amphetamine and morphine would
be in ionized form at the low pH of stomach and not
well absorbed.
O 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.

20. Presence of food and other drug in GIT
O 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, aspirin.
O The presence of other drugs in GIT may increase or
decrease the absorption of drug due to drug-drug
interaction. e.g. Vitamin C enhances the absorption
of iron from the G.I.T. Calcium present in milk and in
antacids forms insoluble complexes with the
tetracycline antibiotics and reduces their absorption.

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

22. Disease states of GIT organs
O Absorption and first pass metabolism may
be affected in conditions like
malabsorption, thyrotoxicosis,
achlorhydria and liver cirrhosis.

23. GIT motility
O Increase in G.I.T. motility as in diarrhoea,
decreases absorption of drugs due to rapid
elimination in faeces. Vomiting also decreases
absorption of drugs.

24. First pass metabolism
O Some drugs e.g. nitroglycerin, isoprenaline,
propranolol, chlorpromazine etc. undergo first
pass metabolism in G.I.T. and liver during
hepatic portal circulation.
O It decreases their therapeutic effect. These
drugs are better administered sublingually to
reach the systemic circulation.

26. Physical state of drug
O Drugs given in liquid dosage form are
better and rapidly absorbed from G.I.T.
than when given in solid dosage forms.

27. Water or lipid solubility of drug
O The biological cell membrane, mucous membrane
and blood capillary membrane are made up of
lipid bilayer. The principle is that: “Cell
membranes are more permeable to unionized
form of a drug than to an ionized form.”
O If the drug is lipid soluble then its greater fraction
exists in unionized form. Therefore lipid soluble
drugs are absorbed better and greater extent
because cell membranes are more permeable to
unionized form of a drug.
O If the drug is water soluble then its greater fraction
exists in ionized form. Hence because of
ionization water soluble drugs poorly absorbed.

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

29. Molecular weight
O Drugs with high molecular weight are not
usually absorbed from gastrointestinal
tract on oral administration.
O Such drugs may be inactivated by
enzymatic degradation. e.g. insulin
undergoes enzymatic degradation in G.I.T.
and not effectively absorbed. Hence
insulin is given subcutaneously.

30. Particle size of drug
O Solid dosage form of drugs that contain smaller
particles are better absorbed from G.I.T. e.g.
aspirin, tolbutamide, griseofulvin. Smaller the
particle size of drug better will be the drug
absorption. Solid dosage form of drugs that
contain larger particles e.g. streptomycin,
neomycin are very little absorbed from G.I.T.

31. Bioavailability
O Bioavailability refers to the rate and extent of
absorption of a drug from a dosage form.
O It is a measure of the fraction (F ) of administered dose
of a drug that reaches the systemic circulation.
Bioavailability of drug injected i.v. is 100%, but is
frequently lower after oral ingestion because-
1) the drug may be incompletely absorbed.
2) the absorbed drug may undergo first pass
metabolism.

32. O Single dose bioavailability test involves an analysis
of plasma or serum concentration of the drug at
various time intervals after its oral administration
and plotting a serum concentration time curve.
AUC after oral dose
AUC after I.V. dose
X 100
Bioavailability
=

34. DRUG DISTRIBUTION
O Drug distribution is the process which transports
a drug to its site of action, to other storage sites
in the body, and to the organs of metabolism
and excretion.

35. The main factors which affect
drug distribution are
O physiochemical characteristics of the drug
O route of drug administration
O plasma proteins binding of drug
O regional blood flow

36. Plasma proteins binding of drug
O After drug get absorbed or injected into systemic
blood circulation, It is distributed in various body fluid
compartments such as interstitial fluid, intracellular
fluid, cerebrospinal fluid, lymph, endolymph, GIT fluid,
aqueous humour, and plasma.
O The plasma and these body fluids contain plasma
proteins albumin, globulin and glycoprotein.
O The drug molecules bound to plasma proteins until
the equilibrium is formed with unbound drug (free
form) in plasma. But the only free drug exerts a
pharmacological action.

37. O Drug bound to proteins forms drug: plasma
protein complex. This complex does not show
pharmacological action, because it cannot cross
cellular membrane to interact with its site of
action.
O Hence Drug: plasma protein complex acts as
drug reservoir. Protein binding slows down
(delay) the drug excretion. Only free drug
capable of crossing cell membrane can show
their pharmacological action.
Drug + plasma protein Drug: plasma protein complex + unbound (free) drug

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

39. METABOLISM OF DRUGS
O The process of alteration in chemical structure
of drug molecule is referred as drug metabolism
or biotransformation.
O Drugs treated by the body as foreign
substances, which body tries to remove from the
body by metabolism and excretion.

40. O The sites for drug metabolism are liver,
kidney, gastrointestinal tract, lungs and
plasma. The metabolism generally results
in the conversion of a drug to a metabolite
that is less active, less lipid soluble, less
toxic and hence easily excreted.
Drug Metabolism
lessactivemetabolite excretion

41. Enzymes responsible for metabolism of drugs:
O a) Microsomal enzymes: Present in the smooth
endoplasmic reticulum of the liver, kidney and
GIT e.g. glucuronyl transferase, dehydrogenase ,
hydroxylase and cytochrome P450.
O b) Non-microsomal enzymes: Present in the
cytoplasm, mitochondria of different organs. e.g.
esterases, amidase, hydrolase.

42. Types of biotransformation
O The chemical reactions involved in
biotransformation are classified as phase-I and
phase-II (conjugation) reactions. In phase-I
reaction the drug is converted to more polar
metabolite.

43. If this metabolite is sufficiently water soluble, then
it will be excreted in urine. Some metabolites may
not be excreted and further metabolised by
phase –II reactions.
O Phase-I: Oxidation (hydroxylation,
dealkylation, deamination,
dehalogenation, sulfoxide formation),
reduction and hydrolysis.
O Phase-II: Glucuronidation, sulfate
conjugation, acetylation, glycine
conjugation and methylation reactions.

44. First pass metabolism
O First pass metabolism is a process in which a drug
administered by mouth is absorbed from the
gastrointestinal tract and transported via portal vein
to liver, where it is metabolized. As a result only a
small fraction of the active drug enters into systemic
circulation and available at its site of action. First
pass metabolism reduces bioavailability of drug. First
pass metabolism can be bypassed by giving the drug
via sublingual or other route.
O E.g. metoprolol, imipramine, cimetidine, diazepam,
nitroglycerin etc.

45. DRUG EXCRETION
O Excretion of drugs means the
transportation of drug metabolite out of
the body. The major processes of
excretion include renal excretion, biliary
excretion and pulmonary excretion. The
minor routes of excretion are saliva,
sweat, tears, breast milk, vaginal fluid,
and hair.

46. 1) Renal excretion:
The excretion of drug by the kidney involves three
stages-
O Glomerular filtration:
some drugs and drug metabolites undergo
ultrafiltration in glomerulus and enter into
glomerular filtrate. All the drugs which have low
molecular weight (5000-69000) can filter through
glomerulus. Only the free form of drug (which is not
bound with the plasma proteins) can pass through
glomerulus.
e.g. phenobarbitone, digoxin, ethambutol etc.

47. O Tubular reabsorption: The reabsorption of drug
takes place from the distal convoluted tubules into
plasma. The unionized and lipid soluble drugs in
the glomerular filtrate rapidly and completely
reabsorbed into blood.
O Tubular secretion: The cells of the proximal
convoluted tubule transport drugs from the
plasma into the tubule e.g. sulpha drugs,
cephalosporin, acetazolamide, penicillin-G,
dopamine, pethidine, thiazides etc.

48. Biliary excretion:
O Molecular weight more than 300 daltons
and polar drugs are excreted in the bile.
After excretion of drug through bile into
intestine, and then excreted in the faeces.
e.g. chloramphenicol

49. Gastrointestinal excretion:
O When a drug is administered orally, a part
of the drug is not absorbed and excreted
in the faeces. e.g. aluminium hydroxide,
ferrous sulphate.

50. Pulmonary excretion:
O Drugs that are readily vaporized, such as
many inhalation anaesthetics and alcohols
are excreted through lungs. E.g. general
anaesthetics, alcohol

51. Sweat
O A number of drugs are excreted into the
sweat e.g. rifampicin, metalloids like
arsenic and other heavy metals.

52. Mammary excretion:
O Many drugs mostly weak basic drugs are
accumulated into the milk. They may enter into
baby through breast milk and produce harmful
effects in the baby
O e.g. ampicillin, aspirin, chlordiazepoxide,
tetracycline, diazepam, furosemide, morphine,
streptomycin etc.

53. OThe End