Factors affecting drug metabolism

Prepared by: JALDIP PATEL

Factors that influence the rate of drug metabolism

I.

Physicochemical properties of drug

II.

Chemical factors a) Induction of drug metabolising enzymes b) Inhibition of drug metabolising enzymes c) Environmental chemicals
Biological factors a) Species difference b) Strain difference c) Sex difference d) Age e) Diet

III.

Contd
f)

Altered physiological factors Pregnancy Hormonal imbalance Disease state

I. Physicochemical properties of drug

Just as the absorption and distribution of a drug are influenced by its physicochemical properties so is its interaction with the drug metabolising enzymes. Molecular size and shape, acidity/basicity, lipophillicity and steric and electronic characteristic of a drug influence its interaction with the active site of enzyme. Stereochemical nature of drug also influence its metabolism where spatial arrangement is critical. Eg. verapamil

II.Chemical factors
a)

Induction of drug metabolising enzymes

The phenomenon of increased drug metabolising ability of the enzymes by several drug and chemicals is called as enzyme induction and the agents which bring about such an effect are known as enzyme inducers.

Properties of enzyme inducers

They are lipophilic compounds. They are substrate for the inducted enzyme system. They have long elimination half lives.

Mechanism involved in enzyme inducers

Increase in both liver size and liver blood flow Increase in both total and microsomal protein content Increased stability of enzyme Increased synthesis and decreased degradation of CYP-450 Proliferation of smooth endoplasmic reticulum

Categories of inducers

There are two categories 1. Phenobarbital type inducer -includes pestisides and several drugs II. Polycyclic hydrocarbon type inducer -includes 3 methyl cholanthrene and cigarette smoke

Examples of enzyme inducers

Barbiturates enhances metabolism of Coumarins , Phenytoin , cortisol, etc. Alchohol enhances metabolism of coumarins, phenytoin and phenobarbital Phenytoin enhance metabolism of cortisol , coumarin and contraceptives Cigarette smoke enhance metabolism of nicotine, amino azo dyes

b)

Inhibition of drug metabolising enzymes

A decrease in drug metabolism ability of an enzyme is called as enzyme inhibition.

Two process of inhibition-

A. Direct inhibitionOccurs by three mechanism:

Competitive inhibition Non competitive inhibition Product inhibition

Contd

B. Indirect inhibition Occurs by two mechanism:

Repression Altered physiology

Note:- Enzyme inhibition is more important clinically than enzyme induction.

Examples of enzyme inhibitors

Coumarins decrease metabolism of phenytoin MAO inhibitors decrease metabolism of barbiturates and tyramine Allopurinol decrease metabolism of 6mercaptopurine

c) Environmental chemicalsSome environmental chemicals influence drug metabolising ability of enzymes.

Examples

DDT and polycyclic hydrocarbons contain in cigarette smoke are enzyme inducers. Organophosphate insecticides and heavy metals like arsenic, mercury, tin and nickel inhibit drug metabolising ability of enzyme.

III.Biological Factors
a)

Species difference It is observed in both Phase I and Phase II reactions. Eg. In phase1 reaction ,Amphetamine and ephedrine are metabolised by oxidative deamination in men and metabolised by aromatic oxidation in rat. In phase II ,phenol is excreted via In pig - glucoronide conjugation

Sex difference Eg. Women metabolise benzodiazpines slowly than men. c) Age In neonates (upto 2 months) the microsomal enzyme is not fully developed and many drugs are biotransformed slowly. Eg. Caffeine has half life of 4 days in neonates compared to 4 hours in adults. due to these sulfonamide leads to renal toxicity and paracetamol leads hepatotoxicity. d) Diet Eg. Low protein diet decrease and high
b)

this is because the enzyme synthesis is promoted by protein diet & raises amino acids levels for conjugation with drugs.

e) Strain difference/ Pharma cogenetics A study of inter-subject variability of drug respon is called as pharmacogenetics. Eg. Metabolism of phenytoin, sulfadimidine, dapsone etc exhibits pharmacogenetic difference.

f) Altered physiological factors Pregnancy Drug metabolising ability of enzyme is reduced during later stages of pregnancy. Eg. Metabolism of promazine and pethidine is

 Hormonal imbalance Higher levels of one

hormone may inhibit the activity of few enzymes while inducing others. Eg. Alloxan induce diabetes show impairment in enzymatic activity with a subsequent fall in the rate of metabolism.

Disease state Due to enhanced half lives of all drugs. Reduction in hepatic drug metabolising

ability in conditions such as hepatic carcinoma, hepatic cirrhosis , obstructive jaundice ,etc. Reduction in renal drug metabolising ability in conditions of renal diseases. Eg. Oxidation of vit. D and hydrolysis of procain.