Enzyme Induction, Enzyme Inhibition and Kinetics of Elimination

Microsomal Enzymes: Microsomal enzymes are the enzymes that are located on the microtubules inside the cell, primarily in the liver, also in the kidney, intestines, and lungs. Cytochrome P450, UGTs, epoxide hydrolases, and mono-oxygenases, etc. are examples of microsomal enzymes. Microsomal enzymes are administered by drugs, diets and other agencies.

Microsomal Enzyme Induction
Many drugs, pollutants( insecticides and carcinogens) interact with DNA and enhance the synthesis of microsomal enzymes such as- (cytochrome P450 & UGTs) which results in the metabolism of inducing drugs is increased.

Examples-
Phenobarbitone induces CYP2B1
Rifampin induces CYP2D6
Alcohol & isoniazid induces CYP2E1
Smoking induces CYP1A
Some other enzyme inducers are –Phenytoin, DDT, phenylbutazone, griseofulvin etc.

Effects of Microsomal Enzyme Induction
Decreased intensity and/or duration of action of drugs is inactivated by metabolism.
Increased intensity of action of drugs activated after metabolism.
Tolerance – (Autoinduction)
Endogenous substrates like- steroids, bilirubin metabolized faster.
Chronic toxicity while testing in animals.

Uses of Enzyme Induction
Congenital non-hemolytic jaundice: phenobarbitone is used.
Cushing syndrome: phenytoin is used.
Severe poisonings
Liver disease

Microsomal Enzyme Inhibition
Inhibition of the metabolism of drugs by the use of another drug that uses the same enzyme such as cytochrome P450, UGTs etc. is called microsomal enzyme inhibition.
Enzyme inhibition occurs by the direct effect on the enzyme.
Most of the drugs may inhibit one iso-enzyme while being a substrate to other iso-enzyme.
Examples-
Quinidine inhibits CYP2D6.
Cimetidine, ketoconazole completely inhibits the metabolism of testosterone.
Chloramphenicol
Erythromycin
Ciprofloxacin.

Kinetics of Elimination
Drugs are removed from the body by various elimination processes.
Drug elimination refers to the irreversible removal of the drug from the body by all routes of elimination.
Provides the basis for excogitating dosage regimens and modifies them.
There are three fundamental parameters for kinetics of elimination. These are-
1. Clearance (CL)
2. Bio-availability (F)
3. Volume of distribution (V)

1. Clearance

Clearance of the drug is the theoretical volume of plasma from which the drug is completely removed in unit time.
CL= rate of elimination / C

{where CL= clearance & C= plasma concentration}.

2. Bio-availability

It is the amount of fraction of administered drug that reaches the systemic circulation.
F= AUC(O)*D(I.V)/ AUC(I.V)*D(O)
{Where, F=bioavailability
AUC= area under curve
O=oral
I.V= intravenous}

3. Volume of Distribution

It is defined as the amount of drug in the body which is administered through any specific route to the concentration of the drug that is measured in blood, plasma etc.

Vd = A/C
{where, Vd=volume of distribution
A= amount of drug in the body
C= plasma concentration}.

1st Order Kinetics

The rate of elimination is directly proportional to the drug concentration.
A) Clearance remains constant, or a constant fraction of drugs present in the body get eliminated per unit time.
B) It applies to most of the drugs which don’t saturate the elimination processes like- transporter, enzyme, blood flow etc.

Zero Order Kinetics

The rate of elimination remains constant irrespective of drug concentration.
A) With an increase in concentration clearance decreases or a constant amount of drug is eliminated from the body.
B) It is also called capacity limited elimination.
C) Enzyme saturate = increase in a dose which further increases plasma drug concentration
Examples- ethanol, heparin, phenytoin, aspirin, theophylline, tolbutamide etc.

Plasma Half-Life
The plasma half-life is defined as the time is taken for its plasma concentration to be reduced to half of its original or initial value. This phase shows declination i.e rapid declining & slow declining.
- In 1st order kinetics, the half-life of the drug doesn't change or remains constant (V and CL remain unchanged).
- In zero-order kinetics, the half-life of the drug increases (CL decreases as the dose is increased).

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