Description on inhibition and induction of drug metabolism

1. INHIBITION AND INDUCTION OF
DRUG METABOLISM
Dr. Ramesh Bhandari
Asst. Professor
Department of Pharmacy Practice
KLE College of Pharmacy, Belagavi

2. INHIBITION OF DRUG METABOLISM
The phenomenon of decreased drug metabolizing ability of
the enzymes by several drugs and chemicals is called as
enzyme inhibition.
The process of inhibition may be of two types:
1)Direct Inhibition
2)Indirect Inhibition

3. DIRECT INHIBITION
 It may result from the interaction of enzyme site, the outcome being a change in
enzyme activity, direct inhibition can occur by one of the three mechanisms.
A. Direct Inhibition:
1. Competitive Inhibition: Eg: Methacholine competes with Ach of choline esterase.
2. Non- Competitive Inhibition: Eg: INH inhibits Phenytoin Metabolism.
3. Product Inhibition
B. Indirect Inhibition:
1. Repression
2. Altered Physiology

4. EXAMPLES OF ENZYME INHIBITION:
i. Fluvoxamine doubles the half life of diazepam
ii. Quinidine inhibits the metabolism of Nifedipine or other
calcium channel blocking agents.
iii. Theophylline clearance is decreased by Cimetidine.
iv. Interferon reduces metabolism of theophylline.
v. Cimetidine and Diazepam interaction.

5. INHIBITION OF MONO AMINE OXIDASE (MAOs)
Non-hepatic enzymes can be involved in drug interactions.
Linezolid with serotonergic psychiatric medications like
antidepressant such as citalopram, paroxetine, fluoxetine and
sertraline and other drugs which affects the serotonergic pathway in
the brain can cause serotonin syndrome.
Linezolid is a reversible Mono Amine Oxidase Inhibitor.
Mono Amine Oxidase is responsible for breakdown of serotonin in
the brain.
If MAOI and linezolid is given concurrently the serotonin level will
increases which will lead to serotonin syndrome.

6. INDUCTION OF DRUG METABOLISM
The phenomenon of increased drug metabolizing
ability of the enzymes by several drugs and
chemicals is known as enzyme induction.
Cytochrome P- 450 isozymes are often involved in the
metabolic oxidation of many drugs.
Many drugs can stimulate the production of hepatic
enzymes.

7. Examples of Induction of Drug Metabolism:
Therapeutic doses of phenobarbital and other barbiturates
accelerate the metabolism of coumarin anticoagulants such
as warfarin and substantially reduce the
hypoprothrombinemic effect.
Other drugs known to induce drug metabolism include
carbamazepine, rifampin, valproic acid, and phenytoin.
Enzymatic stimulation can shorten the elimination half-life
of the affected drug. For example, phenobarbital can result
in lower levels of dexamethasone in asthmatic patients
taking both drugs.

8. INHIBITION
OF
BILIARY SECRETION

9. INHIBITION OF BILIARY EXCRETION
 Among all the route of drug excretion, Bile is also one of them.
 Drugs are often conjugated with bile and then excreted from the body in
bile.
 Water soluble drugs and molecular weight greater than 300 D are
largely excreted in bile.
 Excretion of drugs in bile is mainly via transporters such as MDR1 (P-
glycoprotein), MRP1, MRP2, MRP3 etc.
 Hence there is possibility of drug interaction if drugs are given
concomitantly with other drugs by affecting AUC or bioavailability of
unchanged drug.

10. Drug conjugates with glucuronides and then excreted in bile
Excreted in duodenum in the small intestine
Bacteria in the intestinal tract deconjugates into free form of drug
Absorbed again from the small intestine into the enterohepatic circulation

11. HEPATOBILIARY DRUG INTERACTION
The co-administration of drugs which inhibits the co-
transporter involved in biliary excretion of drug which are
substrates of the transporter, leading to elevated plasma
drug concentration.
Eg: Biliary excretion of digoxin is mediated by
P-glycoprotein which are inhibited by Quinidine. Hence
both digoxin and quinidine is given concomitantly digoxin
levels will increase and may show adverse effect.

12. Other inhibitors of P-Glycoprotein are Verapamil and
cyclosporine which acts by different mechanisms.
Verapamil is a competitive inhibitor of this P- glycoprotein
where as cyclosporine inhibit transport function by
interfering with substrate recognition and ATP hydrolysis.
Inhibition of P-Glycoprotein results in decrease in
clearance of drug and lead to increase in drug levels which
may cause toxicity.
Eg: Verapamil increases steady state plasma concentration of
Digoxin due to inhibition of biliary excretion of digoxin.