Chemical factors of Drug

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Chapter: Biopharmaceutics and Pharmacokinetics : Biotransformation of Drugs

Chemical factors of Drug: Induction of Drug Metabolising Enzymes, Inhibition of Drug Metabolising Enzymes, Environmental Chemicals


Induction of Drug Metabolising Enzymes

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

Most enzyme inducers have following properties –

1. They are lipophilic compounds.

2. They are substrate for the inducted enzyme system.

3. They have long elimination half-lives.

Mechanisms involved in enzyme induction are

1. Increase in both liver size and liver blood flow.

2. Increase in both total and microsomal protein content.

3. Increased stability of enzymes.

4. Increased synthesis of cytochrome P-450.

5. Decreased degradation of cytochrome P-450.

6. Proliferation of smooth endoplasmic reticulum.

Two categories of inducers have been defined –

1. Phenobarbital type inducers: includes several drugs and pesticides which increase the rate of metabolism of a large number of drugs. The most thoroughly studied enzyme inducer is phenobarbital which can increase enzyme activity up to 4 times.

2. Polycyclic hydrocarbon type inducers: such as 3-methyl cholanthrene and cigarette smoke which stimulate the metabolic rate of few drugs.

Some drugs such as carbamazepine, meprobamate, cyclophosphamide, rifampicin, etc. stimulate their own metabolism, the phenomenon being called as auto-induction or self-induction.

The most thoroughly studied enzyme inducer is phenobarbital which can increase enzyme activity up to 4 times. An example which shows that enzyme induction can have serious consequences in clinical practice is the inducing effect of phenobarbital on dicoumarol levels. Extreme caution must be exercised when phenobarbital and dicoumarol are co-administered to avoid either failure of the anticoagulant therapy or haemorrhagic crises.

Consequences of enzyme induction includes

·            Decrease in pharmacological activity of drugs

·            Increased activity where the metabolites are active, and

·            Altered physiologic status due to enhanced metabolism of endogenous compounds such as sex hormones.

Some examples of inducers and drugs affected by them are given in Table 5.4.


Inducers of Drug Metabolising Enzyme System and Drugs Commonly Affected by Them

Inhibition of Drug Metabolising Enzymes

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

The process of inhibition may be direct or indirect.

1. Direct Inhibition: may result from interaction at the enzymic site, the net outcome being a change in enzyme activity.

Direct enzyme inhibition can occur by one of the 3 mechanisms –

a. Competitive Inhibition: results when structurally similar compounds compete for the same site on an enzyme. Such an inhibition due to substrate competition is reversible and can be overcome by high concentration of one of the substrates, e.g. methacholine inhibits metabolism of acetylcholine by competing with it for cholinesterase.

b. Non-competitive Inhibition: results when a structurally unrelated agent interacts with the enzyme and prevents the metabolism of drugs. Since the interaction is not structure-specific, metals like lead, mercury and arsenic and organophosphorus insecticides inhibit the enzymes non-competitively. Isoniazid inhibits the metabolism of phenytoin by the same mechanism.

c. Product Inhibition: results when the metabolic product competes with the substrate for the same enzyme. The phenomenon is also called as autoinhibition.

Certain specific inhibitors such as xanthine oxidase inhibitors (e.g. allopurinol) and MAO inhibitors (e.g. phenelzine) also inhibit the enzyme activity directly. Direct enzyme inhibition is usually rapid; a single dose of inhibitor may be sufficient to demonstrate enzyme inhibition.

2. Indirect Inhibition: is brought about by one of the two mechanisms

a. Repression: is defined as the decrease in enzyme content. It may be due to a fall in the rate of enzyme synthesis as affected by ethionine, puromycin and actinomycin D or because of rise in the rate of enzyme degradation such as by carbon tetrachloride, carbon disulphide, disulphiram, etc.

b. Altered Physiology: due to nutritional deficiency or hormonal imbalance.

Enzyme inhibition is more important clinically than enzyme induction, especially for drugs with narrow therapeutic index, e.g. anticoagulants, antiepileptics, hypoglycaemics, since it results in prolonged pharmacological action with increased possibility of precipitation of toxic effects.

Some examples of inhibitors and drugs affected by them are given in Table 5.5.


Enzyme Inhibitors and Drugs Affected by them

Inhibitors : Drugs with Decreased Metabolism

MAO inhibitors : Barbiturates, tyramine

Coumarins : Phenytoin

Allopurinol : 6-Mercaptopurine

PAS : Phenytoin, hexobarbital

An important example of clinically significant enzyme inhibition is the effect of phenylbutazone on warfarin plasma levels. Warfarin is used as racemic mixture, with the S isomer being 5 times more active than the R isomer. Moreover, warfarin is eliminated from the body almost exclusively by metabolism and the S isomer is metabolised more rapidly that the R isomer. The effect of phenylbutazone on increased levels of warfarin can thus be concluded as –

·            Increase in R isomer levels is due to its displacement from the plasma proteins (little increase in anticoagulant activity).

·            Increase in S isomer levels is due to inhibition of metabolism, with tremendous increase in anticoagulant activity and tendency to cause haemorrhage.

Environmental Chemicals

Several environmental agents influence the drug metabolising ability of enzymes.

·            Halogenated pesticides such as DDT and polycyclic aromatic hydrocarbons contained in cigarette smoke have enzyme induction effect.

·            Organophosphate insecticides and heavy metals such as mercury, tin, nickel, cobalt and arsenic inhibit drug metabolising ability of enzymes.

Other environmental factors that may influence drug metabolism are temperature, altitude, pressure, atmosphere, etc.

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