GOOD MORNING

BIOTRANSFORMATION

BY - MADHU SHARMA
 BIOTRANSFORMATION
(Metabolism of drugs)
DEFINITION-
It is the process of biochemical transformation of drug
from one chemical form to another.
• Drugs are converted into more polar , water soluble
compounds so that they are easily excreted.
• There is conversion of lipophilic drugs to hydrophilic
drugs(as only water soluble drugs are excreted).
• Protects the body from harmful effects of drugs and
chemicals.
• Onset of action of drugs depend on absorption
and distribution of drugs whereas duration and
intensity of drug action depends metabolism and
excretion of drugs.
• Drugs which does not undergoes metabolism are-
streptomcin,neostigmine (highly polar drugs)
 SITE:
• Liver is the most important site becoz enzymes
necessary for metabolism are present in liver.
• Other sites-
gut wall,kidneys,plasma -extrahepatic sites
• Most of the drugs are metabolized by
microsomal enzyme system
• Some are metabolized by non-microsomal and
microfloral systems
 CONSEQUENCIES/OUTCOMES
OF DRUG METABOLISM
1. Active drug is converted into inactive
metabolite-

eg- salicyclic acid - salicyluric acid

phenytoin - β-hydroxy phenytoin
phenobarbital- hydroxyphenobarbital
morphine - hydroxymorphine
2) Active drug converted into active
metabolite-
Eg- digitoxin – digoxin
imipramine – desipramine
codein - morphine
diazepam – temazepam
phenylbutazone - oxyphenylbutazone
 3) Inactive into active drugs-
Eg- L –dopa – dopamine
prednisone - prednisolone
enalapril - enalaprilat
phenacetin – paracetamol
pivampicillin – ampicillin
(PRODRUGS)-these are pharmacologically inactive
drugs which undergoges activation after metabolism.
Advantages of prodrugs-
1. More stable
2. Better bioavailability
3. Less toxic
4. To improve the taste
4) Change in pharmacological activity-
Eg- iproniazid – isoniazid
(antidepressant) (anti-TB)
Diazepam -oxyzepam
ENZYMES IN BIOTRANSFORMATION -

MICROSOMAL- enzymes are located in

liver microsomes.
Cytochrome p450 family are imp.enzymes of BT

NON-MICROSOMAL –enzymes are located

in the cytoplasm nd mitochondria of liver cell
also in plasma nd other tissues
 REACTIONS OF
BIOTRANSFORMATION-
1) Phase I / Non synthetic / Functionalization
a) Convert the drug to more polar metabolite.
b) If the metabolite is not sufficiently polar to be
excreted,it undergoes phase 2 reactions

2) Phase II / Synthetic / Conjugation-

a) Drug form complexes with organic compounds
like glucuronic acid,acetyl,glycine etc.
b) This process results in the inactivation of drugs
 PHASE-1
Oxidation-alcohol, phenytoin, diazepam
,paracetamol
Reduction-chloamphenicol,halothane
Hydrolysis-acetylcholine, aspirin,
penicillin G
Cyclization-proguanil
Decyclization-phenytoin,barbiturates
 PHASE-2
Amino acid conjugation -salicyclic acid,
benzoic acid
Acetylation –sulphonamide,isoniazid
Methylation-adrenaline ,histamine ,dopamine
Sulfate conjugation-paracetamol,steroids
Glucuornide conjugation-
morphine,diazepam,aspirin
 ENZYME INDUCTION-
• Repeated administration of certain drugs increases the
synthesis of microsomal enzymes, This is k/as enzyme
induction
• The drug is referred as enzyme inducers.
• Eg- rifampicin,phenytoin,barbiturates etc.
• This process speeds up biotransformation
 Outcomes of enzyme induction-

1) it decreases the intensity and duration of action of a

drug resulting in therapeutic failure. Eg- rifampicin
2)It increases the intensity nd duration of action of
prodrugs
3)dev.of drug tolerance
4)It can also results in the toxicity due to production of
higher amount of toxic intermediate metabolites
 ENZYME INHIBITION-
• Certain drugs inhibit the activity of drug
metabolizing enzyme and are k/as enzyme
inhibitors.
• Some drugs inhibit cytochrome P450 enzyme
activity.
• Drugs like cimetidine,ketoconazole bind to
cytochrome and competatively inhibit the
metabolism of endogenous substances like
testosterone.
• Outcome- prolonged action and drug toxicity
 ENZYME INDUCERS &INHIBITORS
INDUCERS INHIBITORS
 Rifampicin  Verapamil
 Barbiturates  Erythromycin
 Phenytoin  Cimetidine
 Alcohol  Ketoconazole
 Nicotine  Ciprofloxacin
 Carbamazepine
 Cigratte
 FACTORS INFLUENCING
BIOTRANSFORMATION-
1)Genetic factors-
genetic abnormalites in the cytochrome P450
&glucuronyl transferase can affect phase1 & phase2
reactions of metabolism.
eg-
succinylcholine is metabolized very slowly in people with
defective pseudocholineesterase resulting in prolonged
apnea
2)Environmental pollutants-
like cigarette smoke causes enzyme induction
3)Drug interaction-
Presence of other drugs may stimulate or slow
down the rate of metabolism
Eg- rifampicilin
alcohol
erythromycin
barbiturates
cemitidine
4)Diseases-
Impaired liver function can also slow metabolic
rates.
Rate of metabolism also depends on hepatic
circulation.
5)Age-
Multiple enzyme system become weak in elderly
persons.
Diazepam,barbiturates,imipramine&propanolol to
be given in small doses