This presentation deals with the basic pharmacokinetics principles and concepts for MBBS undergrads

1. Pharmacokinetics
Dr. Karun Kumar
JR-II
Dept. of Pharmacology

2. Definition
• Absorption  Movement of drug into the
bloodstream
• Distribution  Drug leaving the bloodstream and
going into the organs and tissues
• Elimination  2 processes: biotransformation
(metabolism) of a drug to one or more metabolites,
primarily in the liver, and the excretion of the
parent drug or its metabolites, primarily by the
kidneys.

4. Absorption
• Passage of drug molecules from the site of
administration into the circulation
• Applies to all routes except topical & i.v.

5. Processes of absorption
1. Passive diffusion  Fick’s law (Rate of absorption
∝ i) drug conc. Gradient
ii) Surface area for absorption
a) Lipid diffusion  Drug dissolves in lipid
component of cell membrane
b) Aqueous diffusion  Passage through
aqueous pores in cell membrane

6. 2. Active transport (5-FU)
 Requires carrier molecule
 Req. energy (hydrolysis of ATP)
 Against conc. Gradient
3. Facilitated diffusion
 Req. carrier mo.
 No energy reqd.
 not against conc. gradient

7. Effect of pH
• Drugs are weak acids/bases existing in nonionized
& ionized form in body
• Nonionized form crosses membrane lipids

9. Drug distribution
• Drugs are distributed to organs and tissues via the
circulation, diffusing into interstitial fluid and cells
from the circulation.
• ATP-driven drug efflux pumps, known as ABC
transporters (ABC is an acronym for “ATP-binding
cassette”).
• The most studied of these proteins, called
permeability glycoprotein or P-glycoprotein (Pgp),
is expressed on the luminal side of endothelial cells
lining the intestines, brain capillaries, and a number
of other tissues.

10. • Drug transport in the blood-to-lumen direction leads to
a secretion of various drugs into the intestinal tract,
thereby serving as a detoxifying mechanism.
• Pgp also serves to exclude drugs from the brain.
• The Pgp proteins exclude drugs from tissues
throughout the body, including anticancer agents from
tumors, leading to chemotherapeutic drug resistance.
• Inhibition of Pgp by amiodarone, erythromycin,
propranolol, and other agents can increase tissue levels
of these drugs and augment their pharmacologic
effects

12. Factors affecting distribution
1. Organ blood flow  Rapidly distributed to highly
perfused tissues (brain, heart, liver, and kidney) ;
More slowly to less perfused tissues (skeletal
muscle) and even more slowly to those with the
lowest blood flow (skin, bone, and adipose
tissue)
2. Plasma protein binding  Acidic drugs bind to
albumin and basic drugs to glycoproteins and β-
globulins

13. 3. Molecular size  Affects distribution of extremely
large molecules (heparin)
4. Lipid solubility  BBB (Formed by tight junctions
between the capillary endothelial cells and also by
the glial cells that surround the capillaries) which
inhibit the penetration of polar molecules into brain
neurons.

14. Drug biotransformation
• Biotransformation/drug metabolism  Enzyme-
catalyzed conversion of drugs to their metabolites.
• Liver, gut, kidneys, brain, lungs, and skin
• Phase I Rx  Oxidative, hydrolytic & reduction rxns

15. 1st pass metabolism

16. Phase I biotrans
1. Oxidative rx  Most common type of phase I rx
catalyzed by microsomal cytochrome P450 (CYP)
monooxygenase system CYP1, CYP2, and CYP3.
Eg:- codeine, ppnl,Ibuprofen
2. Hydrolytic rx  Esters & amides (Lidocaine,
Procainamide, Aspirin, Esmolol)
3. Reductive rx  Chloramphenicol & Nitroglycerine

17. Phase II biotransf.
• Conjugation with acetate, glucuronate, sulfate, or
glycine (+nt in cytoplasm exc. Glucuronosyl
transferase in SER)
• Most metabolites r inactive
1. Glucuronide  PCM, Morphine, Oxazepam
2. Acetylation  SHIP
3. Sulfation  Acetaminophen, minoxidil,
triamterene

18. Pharmacogenomics
1. Variations in Acetyltransferase Activity  Slow
acetylators (SAs) identified by neuropathic effects
of isoniazid, is autosomal recessive.About 15% of
Asians, 50% of Caucasians and Africans, and more
than 80% of Mideast populations have the SA
phenotype. Other drugs that may cause toxicity
in the SA patient are sulfonamide antibiotics, the
antidysrhythmic agent procainamide, and the
antihypertensive agent hydralazine.(SHIP)

19. Variations in CYP2D6 and
CYP2C19 Activity
• Genetic polymorphisms of CYP2D6 and CYP2C19
enzymes are well characterized, and human
populations of “extensive metabolizers” and “poor
metabolizers” have been identified.
• CYP2D6 substrates  Majority are extensive
metabolizers but 10% of Caucasians and a smaller
fraction of Asians and Africans are poor
metabolizers (Psychotropic drug, codeine)
• Poor metabolizers of CYP2C19 substrates have
higher plasma levels of omeprazole & vice versa

20. • About 1 in 3000 individuals exhibits a familial
atypical cholinesterase that will not metabolize
succinylcholine. Affected individuals are subject to
prolonged apnea after receiving the usual dose of
the drug.
• TPMT (Thiopurine S-methyl transferase) for 6-mp
and azathio. In Caucasians, the most common
variant allele for TPMT is TPMT*3A. Subjects
homozygous for TPMT*3A are at greatly increased
risk for life-threatening myelosuppression when
treated with standard doses of thiopurine drugs.

22. Drug excretion
• Routes of exc.  urine, bile, sweat, saliva, tears,
feces, breast milk, and exhaled air.
1. Glomerular Filtration  free drug enters the
renal tubule as a dissolved solute in the plasma
fitrate
2. Active Tubular Secretion  secretion of
penicillins is inhibited by probenecid.
3. Passive Tubular Reabsorption  Depends on the
lipid solubility of the drug
Drug elim. = Drug m-bol. + exc.
Removal of drugs from body fluids

23. Clearance
• Measure of the rate of elimination
• volume of body fluid (blood) from which a drug is
removed per unit of time
• Calculated by dividing the excretion rate (1200
mg/min) by the plasma drug concentration (3
mg/mL). The result is 400 mL/min, which is equal
to 24 L/hr.

24. Quantitative pharmacokinetics

27. The volume of distribution (Vd) is defined as
the volume of fluid in which a dose of a drug
would need to be dissolved to have the same
concentration as it does in plasma

28. Steady state principle
• Drug is 1st admin  Rate of admin. > Rate of elim.
• As the drug continues to be administered, the rate
of drug elimination gradually increases, whereas
the rate of administration remains constant.
• Eventually, as the plasma concentration rises
sufficiently, rate of drug elim = rate of admin.
• At this point the steady-state equilibrium is
achieved.