This document discusses pharmacokinetics and biotransformation. It covers the four main stages of pharmacokinetics: absorption, distribution, metabolism, and excretion. Metabolism, or biotransformation, involves enzymatic conversion of drugs by the liver and involves two phases - phase I and phase II reactions. Phase I introduces or exposes functional groups using oxidation, reduction or hydrolysis. Phase II involves conjugation reactions like glucuronidation and sulfation. Cytochrome P450 enzymes and microsomal enzymes are responsible for many phase I reactions. Factors like enzyme induction and inhibition can impact drug metabolism and clearance from the body.

1. PHARMACOKINETICS- II
Dr. POOJA. M

2. Pharmacokinetics
 Includes:
•Absorption
•Distribution
•Metabolism (Biotransformation)
•Excretion.

4. BIOTRANSFORMATION

5. •Involves enzymic conversion of one chemical entity to
another within the body.
• Occurs between absorption of the drug into the
circulation and its elimination.
• Renders non polar (lipid soluble) compounds polar
(lipid insoluble).
• Sites- liver, GIT, lungs, kidneys, brain, skin.

6. Consequences in a biotransformation reaction:
 Formation of an inactive metabolite from a
pharmacologically active drug.
Eg: 6- Mercaptopurine 6- Mercapturic acid
(Active drug) (Inactive metabolite)
Formation of an active metabolite from an inactive or a
lesser active drug.
Eg: L- dopa Dopamine in basal ganglia
(Inactive) (Active)

7. Formation of an active metabolite from an equally
active drug.
Eg: Diazepam Oxazepam
(Active) (Active metabolite)
 Formation of a toxic metabolite from an active drug.
Eg: Paracetamol N- acetyl- p- benzoquinoneimine
(Active) (Toxic metabolite)

8. MICROSOMAL ENZYMES
• Drug metabolizing enzymes associated with smooth
endoplasmic reticulum of the liver.
•Principal enzymes involved:
- Mixed Function Oxidase
- Cytochrome P450
•Non specific in action.
•Can be induced, activated. Can metabolize only lipid
soluble drugs.
•Primarily concerned with phase I oxidation and
reduction.

9. The activity of MFO’s require a reducing agent
(nicotinamide adenine dinucleotide phosphate [NADPH])
and molecular oxygen.
In a typical reaction, one molecule of oxygen is
consumed (reduced) per substrate molecule, with one
oxygen atom appearing in the product and the other in
the form of water.
Drug + O2 + NADPH + H+ Drug metabolite + H2O +
NADP+

10. Cytochrome P450 abbreviated as P450 or CYP- a
haemoprotein.
Classified into families designated as 1,2,3,4 and
subfamilies by letters A, B, C, D.
Another number is added to indicate specific
isoenzyme. Eg: CYP2A6.

12. These enzymes differ from one another in:
 Amino acid sequence.
Sensitivity to inhibitors and inducing agents.
Specificity of the reactions they catalyse.

13. Biotransformation reactions- 2 types:
 Phase I/ Non synthetic reactions
Phase II/ Synthetic reactions

15. PHASE I REACTIONS
 Functions to convert lipophilic molecules into polar
molecules by introducing or unmasking a polar
functional group like –OH or –NH2 .
Involves Oxidation, Reduction and Hydrolysis.

16. OXIDATION:
 Microsomal oxidation causes aromatic or aliphatic
hydroxylation, deamination, dealkylation or S-oxidation.
These reactions involve reduced nicotinamide adenine
dinucleotide phosphate(NADP), molecular O2 and one
or more group of CYP450.
Drug + O2 + NADPH + H+ Drug- OH + H2O + NADP+
Can also involve other MFO’s like flavin containing
monooxygenases or epoxide hydrolases.

19. REDUCTION:
Reduction requires reduced NADP-cytochrome-c
reductase or reduced NAD-cytochrome b5 reductase.
HYDROLYSIS:
 These reactions do not involve hepatic microsomal
enzymes.
Occur in plasma and other tissues.
Both ester and amide bonds are susceptible to
hydrolysis.

21. PHASE II REACTIONS
 Consists of conjugation reactions.
Drugs already possessing an –OH, -NH2 , -COOH
group may enter phase II directly without prior phase I
metabolism.
Involves acetylation, methylation, glucuronidation,
sulphation, mercaptopuric acid formation, glutathione
conjugation.

22. AMINO ACID REACTIONS:
 Glycine and glutamine are chiefly involved.
Glycine forms conjugates with nicotinic acid and
salicylates.
Glutamine forms conjugates with p-aminosalicylates.

23. ACETYLATION:
Acetate derived from acetyl coA conjugates with drugs
like isoniazid, sulfonamides.
This activity resides in the cytosol and occurs in the
leucocytes, gastrointestinal epithelium and the liver.

24. GLUCURONIDATION:
Catalysed by UDP- glucuronyl tranferase enzyme.
Conjugation reactions between glucuronic acid and
carboxyl groups are involved in the metabolism of
bilirubin, diazepam etc.

25. Deficiency of glucuronide formation
Excess unconjugated bilirubin
Non hemolytic jaundice

26. METHYLATION:
 Proceeds by a pathway involving S-adenosyl
methionine as methyl donor to drugs with free amino,
hydroxyl or thiol groups.
 Eg: Catechol-O-methyl transferase.
 Present in the cytosol.

27. Methylates the terminal – NH2 residue of noradrenaline
to form adrenaline in the adrenal medulla
Catalyses the transfer of a methyl group to
catecholamines, inactivating noradrenaline, dopamine
and adrenaline.

29. ENZYME INDUCTION
Some P450 substrate drugs, on repeated
administration induce P450 expression by enhancing the
rate of its synthesis.
Leads to accelerated drug metabolism leading to:
 Decreased plasma drug concentrations.
Decreased drug activity if metabolite is inactive.
Increased drug activity if metabolite is active.
Decreased therapeutic drug effect.

30. CLINICAL RELEVANCE
Drug- drug interaction:
Eg: Phenytoin accelerates Vitamin D3 metabolism
Osteomalacia.
Failure of OCP if potent inducers like rifampicin or
phenytoin are used.
Drug toxicity:
Eg: Risk of hepatotoxicity is more in Ethanol drinkers
than in those having Paracetamol overdose.

31. ENZYME INHIBITION
 One drug may inhibit the metabolism of another drug
resulting in an increase in the circulating levels of the
slowly metabolized drug.
A drug may inhibit one isoenzyme while itself being a
substrate of another isoenzyme.
Eg: Quinidine is metabolized mainly by CYP3A4 but it
inhibits CYP2D6.

32.  Inhibition of CYP isoenzyme activity is an important
source of drug interactions that leads to serious adverse
events.
Eg: Omeprazole is a potent inhibitor of 3 CYP
isoenzymes responsible for warfarin metabolism.

34. Inhibition of drug metabolism
Increased plasma levels over time and with long
term medications.
Prolonged pharmacological drug effect.
Increased drug induced toxicities.

35. FIRST PASS METABOLISM
 All drugs taken orally pass through GIT and portal
system before reaching the systemic circulation.
 In first pass metabolism, metabolism of drugs occur
before the drug enters systemic circulation.
Net result is decreased bioavailabilty of the drug
leading to diminished therapeutic response.

37. EXCRETION OF DRUGS

38.  Most drugs and drug metabolites are eliminated from
the body through renal (most common) and biliary
excretion.
 Relies on the lipophilic character of the drug or
metabolite.

39. RENAL EXCRETION OF DRUGS:
Renal blood comprises 25% total systemic blood flow.
Rate of drug elimination through kidneys depend on:
 balance of drug filtration
 secretion
 reabsorption rate.

40. Afferent arteriole Free drug and plasma protein
bound drug glomerulus.
 However only the free drug is filtered into the renal
tubule.
 Renal blood flow, GFR and drug binding to plasma
protein affect the amount of drug entering the tubule at
the glomerulus.

41. Rapid excretion of the drug is caused by:
 Enhancing the blood flow.
Increasing the GFR
Decreasing plasma protein binding.

43. GLOMERULAR FILTRATION:
 Drugs enter the kidney through renal arteries which
divide to form glomerular capillary plexus.
Free drug flows through the capillary slits into the
Bowman’s space as a part of glomerular filtrate.
Glomerular capillaries allow drug molecules of
molecular weight below 20,000.
Lipid solubility and pH do not influence passage of
drugs into the glomerular filtrate.

44. TUBULAR SECRETION:
 Upto 20% of renal plasma flow is filtered through the
glomerulus.
80% pass on to the peritubular capillaries of the
proximal tubules.
 Here, the drug molecules are transferred to the tubular
lumen by two independent and relatively non selective
carrier systems- OAT and OCT.
OAT transports acidic drugs while OCT handles organic
bases.

46.  Unlike glomerular filtration, carrier mediated transport
can achieve maximal drug clearance even when most of
the drug is bound to plasma protein.
Many drugs compete for the same transport system
leading to drug interactions.
Eg: Probenecid prolongs the action of penicillin by
retarding its tubular secretion.

47. TUBULAR REABSORPTION:
 The concentration of the drug increases as it moves
towards the distal convoluted tubule.
If the drug is uncharged, it may diffuse out of the
nephric lumen back into the systemic circulation.
 For an ionised drug, reabsorption in the tubule can be
enhanced or inhibited by chemical adjustment of urinary
pH.

48.  Weak acids can be eliminated by alkanisation of urine
while weak bases can be eliminated by acidification of
urine- ion trapping.
Eg: Phenobarbitol overdose can be treated with sodium
bicarbonate.
It alkanises the urine, keeps the drug ionised and
decreases its reabsorption.
If overdose is with a weak base, such as cocaine,
acidification of the urine with NH4Cl leads to protonation
of the drug and an increase in its clearance.

49. BILIARY EXCRETION:
 Various hydrophilic drug conjugates particularly
glucuronides are concentrated in the bile and delivered
to the intestine.
Here the glucuronide is hydrolysed, releasing the active
drug once more.
This free drug is reabsorbed and the cycle is repeated-
enterohepatic circulation.

51. CLEARANCE
 Defined as the rate of elimination of the drug in relation
to its concentration.
 Clearance = Rate of elimination
Concentration
 Elimination of the drug may involve processes occuring
in the kidney, liver, lungs etc..
Clearance(total) = Clearance(renal) + Clearance (hepatic) +
Clearance(others).

52. KINETICS OF ELIMINATION
 Most of the elimination reactions (includes both
metabolism and excretion) follow Michaelis- Menten
kinetics:
Rate of elimination= E= Vmax [C]
Km+ C
Where,
 Vmax Maximum rate of drug elimination.
 Km drug concentration at which rate of elimination is
½ Vmax (Michaelis constant).
 C Concentration of the drug in the plasma.

53. FIRST ORDER KINETICS:
 Here the concentration of the drug is much less than
the Michaelis constant Km.
Hence the equation reduces to,
E = Vmax [C]
Km
That is, rate of drug elimination is directly proportional
to the concentration of the free drug.

55. ZERO ORDER KINETICS:
 In a few drugs like aspirin, ethanol and phenytoin,
[C] is much greater than Km.
 Hence the equation reduces to,
E = Vmax [C] = Vmax
[C]
 Rate of elimination remains constant over time.

56. REFERENCES:
 Rang and Dales pharmacology.
 Basic and clinical pharmacology – Katzung.
Lippincott’s illustrated reviews.
 David E Golan’s Principles of pharmacology.
 Text book of clinical pharmacolgy- James Ritter
HL Sharma
KD Tripathi

57. THANK YOU…