Biotransformation of drugs

1. BIOTRANSFORMATION OF
DRUG
By
Sachchidanand Pathak
KIP

2. INDEX
1. Introduction
2. Drug Metabolising Organ
3. Drug Metabolising enzyme
4. Chemical Pathway of Drug Biotransformation
5. Need of Biotransformation
6. Disease Affecting Biotransformation
7. Role of Biotransformation in Drug Development

3. BIOTRANSFORMATION -
It is the process of chemicalbiochemical alteration or
conversion of the drug from one form to another form in the
body.
Most of the hydrophilic drugs (streptomycin, neostigmine,
pancuronium etc.) are little biotransformed and are largely
excreted unchanged.
Body treat the most drugs as foreign substance and tries to
inactivate and eliminate them by various biochemical reaction.
KD.Tripathi &
D.M. Brahmankar

4. Biotransformation of drug may lead to the following:
 Inactivation :
e.g.- salicylic acid (active)-----------salicyluric acid (inactive)
phenytoin (active)--------------p-hydroxy phenytoin (inactive)
 Active metabolite :
e.g.- amitriptyline (active)-----------nortryptiline (same active)
phenylbutazone (active)-------oxyphenbutazone (same active)
 Activation of inactive drug (Prodrug) :
e.g.- enalapril (prodrug)--------------enalaprilat (active)
levodopa (prodrug)--------------dopamine (active)
 Change in pharmacological activity :
e.g.- diazepam (tranquilizer)---------oxazepam (anticonvulsant)
iproniazid (antidepressant)-----isoniazid (antitubercular)
KD.Tripathi &
D.M. Brahmankar

5. Drug Metabolising Organ
Every tissue has some ability to metabolised the drug.
Hepatic metabolism-----------liver
Extrahepatic metabolism-----metabolism by organ other than
liver.
Liver > Lungs > kidney > intestine > placenta > Adrenals > skin
( Brain, testes, muscles, spleen, etc. also metabolised drug but to a small extent.)
D.M. Brahmankar
& B.G.Katzung

6. Drug Metabolising Enzymes
Microsomal enzyme - Located on smooth E.R.(hepatic cell)
e.g.- cytochrome P450, monooxygenases, glucuronyl transferase etc.
Nonmicrosomal enzyme or non specific enzyme – Located on
cytoplasm of mitochondria in soluble form (hepatic cell) not on E.R. .
e.g.- oxidases, esterases, amidases, dehydrogenases, peroxidases etc.
These enzyme are deficient in new born hence making more
susceptible to many drugs.
e.g.- opioid
K.D.Tripathi

7. Chemical Pathway Of Drug Biotransformation
R.T. Williams divided the pathway of drug biotransformation into two general
categories-
I. Phase 1/Nonsynthetic/ Functionalization reaction
II. Phase 2/Synthetic/Conjugation reaction
Phase 1- objectives:
a) Oxidation-e.g. phenytoin, diazepam &ibuprofen.
b) Reduction-e.g. chloramphenicol, halothane & warfarin.
c) Hydrolysis-e.g. aspirin, lidocaine & choline ester.
d) Cyclization-e.g. proguanil.
e) Decyclization-e.g. barbiturates & phenytoin.
KD Tripathi

8. Phase 2-
a) Glucuronide conjugation-e.g. aspirin, PCM & morphine.
b) Acetylation-e.g. sulfonamide & isoniazid.
c) Methylation-e.g. methyldopa, captopril & adrenaline.
d) Sulfate conjugation-e.g. chloramphenicol & methyldopa.
e) Glycine conjugation-e.g. salicylates
f) Glutathione conjugation-e.g. PCM
g) Ribonucleoside/nucleotide synthesis-e.g.warfarin.
KD Tripathi
Goodman & gilman

9. Why Is Drug Biotransformation Necessary?
DRUG
( Lipid-soluble, Nonpolar )
PHASE-1 PHASE-2
BIOTRANSFORMATION SYNTHESIS
Oxidation, hydrolysis conjugation with
Reduction glycine, sulfate &
glucoronic nacid
METABOLITE A METABOLITE B METABOLITE C
WATER SOLUBLE OR POLAR FORM
EXCRETION (URINE & BILE)

10. Diseases Affecting Drug Metabolism
 Liver diseases- hepatitis, cirrhosis, etc.
e.g.- Half-lives of chlordiazepoxide and diazepam are increased then
these drug may cause coma in ordinary dose.
 Cardiac diseases- Impair the disposition of those drug whose
metabolism is flow limited.(by limiting blood flow to the liver)
e.g.-isoniazid, verapamil and disipramine are rapidly metabolised by
liver than hepatic clearence is equal to liver blood flow.
 Pulmonary diseases-
e.g.- Impair the hydrolysis of procainamide and procaine in patient with
chronic respiratory insufficiency.
Increased half-life of antipyrine in patient with lung cancer.
B.G.Katzung

11. ABSTRACT
 Xenobiotics are as a rule lipophilic, well absorbed from the blood,
but excreted slowly in the urine.
 Only after conjugation (Phase 2) reactions have added an ionic
hydrophilic moiety, such as glucuronic acid, sulfate ester, or
glycine, to the xenobiotic is water solubility increased and lipid
solubility decreased enough to make urinary elimination possible.
 The major proportion of the administered drug dose is excreted as
conjugates into the urine and bile.

12. Role Of Biotransformation In Drug Development
Efficacy
Safety
Both depend on drug metabolism
Goodman & Gilman

13. REFERENCE
1. Goodman Louis S. & Gilman Alfred, “The pharmacological basis of
Therapeutics”, eleventh edition, 11,73 & 90.
2. Katzung Bertram G., “Basic and clinical pharmacology”, tenth
edition, 2007, 50-62.
3. Tripathi KD, “Essential of medical pharmacology”, sixth edition,
2008, 23-26.
4. Brahmankar D.M. & Jaiswal S.B., “Biopharmaceutics &
Pharmacokinetics”, second edition, 2009, 139-144.

14. Questions?

15. Thank You