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Metabolism
Dr. Rahul Kunkulol , Asso. professor, Dept. Of Pharmacology
Drug Metabolism /
Biotransformation
The chemical modification of drugs
with the overall goal of getting rid of
the drug
Enzymes are typically involved in
metabolism
Oral
Administration
Biotransformatio Liver
n
Intestines
Consequences Of Metabolism
Phenobarbitone Hydroxyphenobarbitone
(inactive)
Consequences Of Metabolism
The metabolite may have
Equal activity to the drug
Many drugs have been found to be partially
converted to active metabolite.
Examples-
Features:
Toxic properties not seen with the parent drug
Stable drug
Better PK profile and bioavailability.
First Pass Effect
Biotransformation of drug by liver or gut
enzymes before compound reaches
systemic circulation
Results in lower systemic bioavailbility of
parent compound, diminished therapeutic
response.
First pass effect may be bypassed if the
Examples: Propafenone, Isoniazid,
drug is administered IV or Sublingually.
Propanolol
Drug Metabolising
enzymes
Microsomal
Non-microsomal
Non enzymatic
biotransformation
Microsomal cytochrome P450,
monooxygenase family of
enzymes, which oxidize
drugs.
Microsom Location-smooth endoplasmic
al reticulum in Liver, Kidney,
intestinal mucosa, and lungs.
Enzymes
They catalyze:
Oxidation, reduction, hydrolysis
(phase I reactions)
Glucuronide conjugation
(phase II reactions)
Cytochrome P450
Inducer:
Drug that will increase the synthesis of
CYP450 enzymes
Inhibitor
Drug that will decrease the metabolism of
a substrate
Cytochrome P450 expression
CYP2D6
Sub-Family Individual Gene
Enzyme characteristics
% of drugs metabolised by enzyme
3A4 60%
2D6 25%
1A2 15%
2C9 Small no. but significant
interactions
2C19 Small no. but significant
interactions
2E1 ?
Cytochrome P450 expression
Variation in levels, activity due to:
Genetic polymorphism
Environmental factors:
Inducers, inhibitors, disease
Multiple P450s can catalyze same
reaction
A single P450 can catalyze multiple
pathways
Location :
Cytoplasm, mitochondria of hepatic
cells.
Examples :
Non- Monoamine oxidases (MAO), Esterases,
Amidases, Transferases, Conjugages
microsom
Reaction catalysed are all Phase II
al reactions except_?...._____
Enzymes These are noninducible
May show genetic variations
Hoffmans
Elimination
Non Example: some drugs like
enzymatic atracurium (skeletal muscle
bio- relaxant) are metabolized in
transformatio
plasma through molecular
n
rearrangement without
involvement of enzyme
action.
BIOTRANSFORMATION REACTIONS
Nonsynthetic / Phase I:
Metabolite may be active or inactive.