The document discusses biotransformation, which is the biochemical alteration of drugs inside the body. The main site of biotransformation is the liver, with other sites including the kidneys, lungs, intestine, and skin. Biotransformation makes drugs more polar, water soluble, and less lipid soluble to promote excretion. It can convert active drugs into inactive metabolites or active metabolites. The two main phases are phase I reactions, which use oxidation, reduction, and hydrolysis to introduce or remove functional groups, and phase II reactions, which produce non-toxic conjugates through glucoronidation, acetylation, methylation, and other conjugation reactions. Factors that can influence biotransformation include patient factors like age and genetics

1. BIOTRANSFORMATI
ON
Pharmacology & Therapeutics.
EM 16 …A2
PREAENTED BY

2. Biochemical alterations of drug inside the body is called
biotransformation.
 Main Site : Liver
 Other Sites :
• Kidney
 Lungs
 Intestine
 Skin
 Plasma etc.

3. To make the drugs highly polar
More water soluble
Less lipid soluble
•To promote excretion of drugs.
•To convert active drugs into inactive metabolites
Phenobarbitone Hydroxyphenobarbitone
(active) (inactive)
•To convert active drugs into active metabolites
Diazepam Oxazepum
•To convert pharmacologically inactive drugs(prodrugs) into active
compounds
•Levodopa Dopamin

4.  Microsomal Enzymes
 Mixed Functional Oxidase(MFO)
 Glucoronyl transferase
 Dehydrogenase
 Hydroxylase
 Reductase
Sites Smooth Endoplasmic reticulum (liver)
 Non-microsomal Enzymes
 Mono Amino Oxidase(MAO)
 Acetyltransferase
 Methyltransferase
 Glyceine transferase
 Esterase
 Hydrolases
Sites Cytosol , Mitochondria

5. Phases of biotransformation
•Phase I reaction/Non synthetic/ Functionalization
•Phase II reaction/Synthetic/Conjugation
Phase I Reaction
In phase I reaction the parent drugs converts a drug to molar polar compound/
metabolites by introducing or removing polar functional groups.
Example: -OH, -NH2, -SH.
• Phase I reaction involves both microsomal and nonmicrosomal enzyme
reactions.

6.  Oxidation
This reaction involves addition of an oxygen to
and/or removal of a hydrogen molecule.
MFO
Phenacetin Paracetamol
 Reduction
The enzyme responsible is reductase which
catalyzes the reduction of Azo and Nitro groups.
Azo reduction
reductase
Prontosil Sulfonamide

7. Nitro reduction
Chloramphenicol Amino chloramphenicol
 Hydrolysis
Cleavage of drug molecule by taking up a
molecule of water .
acetylcholinesterase
Acetylcholine Choline + Acetate

10. Phase II reaction
* In phase II reaction nontoxic conjugates are produced from
phase I metabolites or parent drug
* Do not involve microsomal enzymes except glucoronide
conjugation
* Metabolites are pharmacologically inactive,more polar and
easily excretable
Conjugates are:
* Pharmacologically inactive
* more polar
* more water soluble
* less lipid soluble
* easily excretable

11. Involved conjugation reactions:
1)Glucoronide conjugation
2)Acetylation
3)Methylation
4)Glyceine conjugation
5)Sulphate conjugation
• Types of conjugation:
A)Glucoronide Conjugation:
Enzyme involved:Glucoronyl transferase
Example of drugs:
Morphine,Chloramphenicol,Bilirubin

12. Clinical significance:
• 1)Morphine is metabolized by glucoronyl transferase enzyme.In
neonates glucoronyl transferase enzyme is deficient.So morphine
will not be metabolized leading to neonatal respiratory depression
• 2)Chloramphenicol is also metabolised by glucoronyl transferase
enzyme.Due to its deficiency chloramphenicol will not be
metabolised leading to gray baby syndrome.
• 3)Due to deficiency of glucoronyl transferase enzyme bilirubin will
not be metabolized.As a result bilirubin will not be excreted from
body leading to hyperbilirubinemia Kernicterus in newborn

13. Gray baby syndrome kernicterus

14. B)Acetylation:
Enzyme: Acetyltransferase
Example:
• Isoniazid
• Sulphonamide
Clinical significance:
1)Isoniazid in rapid acetylators Increased
metabolism of isoniazid leading to produce hepatotoxic
metabolites results in hepatotoxicity
2)Isoniazid in slow acetylators Isoniazid utilizes vit
B6(pyridoxine) for its metabolism results in pyridoxine
deficiency leading to peripheral neuropathy

15. C)Methylation :
Enzyme:Methyl transferase
Example of drugs:
• Adrenaline
• Nor adrenaline
D)Glyceine conjugation:
Enzyme:Glyceine transferase
Example of drugs:
• Salicylates
• Aspirin
E)Sulphate conjugation:
Enzyme:Sulphokinase
Example of drugs:
• Paracetamol
• Steroids

16. Factors Influencing biotransformation:
 Patient factors
1)Extremes of Age & Sex
2)Genetic Factor
3)Disease state
1)Extremes of age and sex:
• Premature:Enzyme system is less developed so metabolism is less developed
eg: In glucoronyl transferase deficiency, chloramphenicol causes gray baby syndrome
• Young:Enzyme system well developed so metabolism is more
• Old age :Reduced enzyme reduced metabolism
• Sex:Metabolism is more in male due to testosterone which induces drug metabolising enzyme

17. 2)Genetic factors:
Variation in response to some drugs may be attributed to genetic polymorphisms.Polymorphism involves:
• Defective oxidation:
Slow oxidisers may show toxic response to standard dose of a drug
Rapid oxidisers may fail to respond to standard dose of drug
eg: Haloperidol(Anasthetic agent)
• Defective acetylation:
Slow acetylators
Rapid Acetylators
eg:Isoniazid
• Glucose 6 phosphate dehydrogenase deficiency
It maintains integrity of RBC .Those who are deficient may suffer from acute hemolysis if exposed to certain drugs
eg:primaquine,sulphonamides

18. • Pseudocholinesterase deficiency:
Neuromascular blocking action of suxamethonium is terminated by
pseudocholinesterase enzyme.Due to its lack metabolism of
suxamethonium is greatly reduced pt fails to breathe
spntaneously after operation results in prolonged apnoea
3)Diseased State:
In liver cirrhosis,cardiac disease ,nephrotic syndrome,
hepatitis metabolism of drugs decrease

19.  DRUG FACTOR
•ENZYME INDUCTION : metabolism increases by enzyme induction.
•ENZYME INHIBITION: metabolism decreases by enzyme inhibition.
PLASMA PROTEIN BINDING: more plasma protein binding less
metabolism/biotransformation
•SEQUESTRATION IN DIFFERENT TISSUES: sequestration of drug in various tissues (adipose
tissue,bone,brain,heart)cause decrease in metabolism.

20. ENZYME INDUCTION
DEFINITION:
Increase synthesis and activity of microsomal enzyme systems
due to repeated administration of certain drugs and chemicals
(inducing agent)resulting increase metabolism of the inducing
agent itself as well as other drugs is known as enzyme
induction.
ENZYME INDUCES:
 Phenobarbitone and other barbiturate
 Rifampicin
 Phenytoin
 Griseofulvin
 Carbamazepine

21. CLINICAL SIGNIFICANCE:
1. THERAPEUTIC FAILURE/DRUG INTERACTION:
Eg: If oral contraceptive pill is given to a TB patient receiving Rifampicin Rifampicin is an enzyme
inducer increase metabolism of ocp result in therapeutic failure of ocp
2. THERAPEUTIC APPLICATION:
Phenobarbitone induces glucoronyl transferase enzyme activity .This enzyme is responsible for billirubin
metabolism .So,phenobarbitone is used to treat hyperbillirubinemia and kernicterous in newborn.
3. DRUG TOXICITY DUE TO ENZYME INDUCTION:
The toxic effect of paracetamol is mediated hepatotoxic metabolite N-acetyl benzoquinine,which is formed
by cyt.p450.Therefore the risk of hepatotoxicity following paracetamol overdose is increased in patients
whose cyt.p450 system has been induced by enzyme inducers.
4. DEVELOPMENT OF TOLERANCE:
Slow development of tolerance of inducing agents due to metabolism of inducing agent itself.

23. ENZYME INHIBITION
Definition: Decrease synthesis & activity of microsomal
enzyme system (cyt.p450) by certain drugs or chemicals
which results in inhibition of metabolism of inhibitory
drug itself as well as other drugs is known as enzyme
inhibition .

24. Important enzyme inhibitors:
 Cimetidine
 Erythromycin
 Metronidazole
 Ciprofloxacin
 Chloramphenicol
 Steroids etc.

25. Clinical significance :
1. Drug interaction:
Increase toxicity of primary drug .
(as inhibitors decrease metabolism of itself as well as
other drugs)
Example: Warfarin+ Cimetidine
Increased blood loss due to toxicity
Increased plasma concentration of warfarin

26. 2.Increase efficacy of primary drug :
Example :
Theophylline +cimetidine
Theophylline is a bronchodilator which is not metabolized
in presence of cimetidine …
Prolonged effect of theophylline.

27. 3.Sometimes it modifies the disease process:
Example :
Allopurinol inhibits the enzyme xanthin oxidase
& therefore reduce uric acid synthesis in vivo.
Thus prevents attack of gout.

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