Biotransformation of drugs is defined as the chemical conversion of one form to another. The term is used synonymously with metabolism,
The therapeutic efficacy, toxicity and biological half-life of a drug greatly depend upon its metabolic rate.
A number of factors may influence the rate of drug metabolism. They are as follows,
Physicochemical properties of the drug
Chemical factors:
Induction of drug metabolizing enzymes
Inhibition of drug metabolizing enzymes
Environmental chemicals
Biological factors:
Species differences
Strain differences
Sex differences
Age
Diet
Altered physiological factors:
Pregnancy
Hormonal imbalance
Disease states
Temporal factors:
Circadian rhythm
Circannual rhythm.
Physicochemical properties of the drug:
Just as the absorption and distribution of a drug are influenced by its physicochemical properties, so is its interaction with the drug metabolizing enzymes.
Molecular size and shape, pKa, acidity/basicity, lipophilicity and steric and electronic characteristics of a drug influence its interaction with the active sites of enzymes and the biotransformation processes to which it is subjected.
Stereochemical nature of the drug also influences its metabolism.
Chemical factors:
Induction of drug metabolizing enzymes
Inhibition of drug metabolizing enzymes
Environmental chemicals
Induction of drug metabolizing enzymes:
Certain drugs stimulate the enzyme system causing increased metabolism, the phenomenon is called enzyme induction and the enzyme is called enzyme inducer.
e.g.
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.
Inhibition of drug metabolizing enzymes:
Certain drugs inhibit the enzyme system causing decreased metabolism, the phenomenon is called enzyme inhibition and the enzyme is called enzyme inhibitor.
e.g.
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:
Occurs 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. PABA and Sulfa drugs.
b. Non-competitive Inhibition:
Occurs 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.
e.g. Isoniazid inhibits the metabolism of phenytoin.
c. Product Inhibition:
Occurs when the metabolic product competes with the substrate for the same enzyme. The phenomenon is also called 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 cause enzyme inhibition.
2. Indirect Inhibition: is caused by one of the two mechanisms –
a. Repression:
It 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, disulfiram, 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, hypoglycemics, since it results in prolonged pharmacological action with increased possibility of toxic effects.
Environmental chemicals:
Several environmental agents influence the drug metabolizing ability of enzymes.
e.g.
Halogenated pesticides such as DDT and polycyclic aromatic hydrocarbons contained in cigarette smoke have enzyme induction effects.
Organophosphate insecticides and heavy metals such as mercury, tin, nickel, cobalt and arsenic inhibit drug metabolizing ability of enzymes.
Other environmental factors that may influence drug metabolism are temperature, altitude, pressure, atmosphere, etc.
3) Biological factors:
Species differences
Strain differences
Sex differences
Age
Diet.
Species differences:
Species differences have been observed in both phase I and phase II reactions.
An example of this is the metabolism of amphetamine and ephedrine.
In men and rabbits, these drugs are predominantly metabolized by oxidative deamination whereas in rats the aromatic oxidation is the major route.
Strain differences:
Enzymes influencing metabolic reactions are under the genetic control.
Just as the differences in drug metabolizing ability between different species are attributed to genetics, so also are the differences observed between strains of the same animal species.
In identical twins (monozygotic), very little or no difference in the metabolism of phenylbutazone, dicoumarol and antipyrine was detected but large variations were apparent in fraternal twins (dizygotic; twins developed from two different eggs) for the same drugs.
Some humans metabolize Isoniazid faster; they are called fast acetylators and while those who show slower metabolism are called slow acetylators.
Age:
Differences in the drug metabolic rate in different age groups are mainly due to variations in the enzyme content, enzyme activity and haemodynamics.
In neonates (upto 2 months), the microsomal enzyme system is not fully developed and many drugs are biotransformed slowly.
chloramphenicol leads to cyanosis or Gray baby syndrome in newborns.
sulfonamides cause renal toxicity and paracetamol causes hepatotoxicity.
Infants (between 2 months and one year) show almost a similar profile as neonates in metabolizing drugs with improvement in the capacity as age advances and enzyme activity increases.
Children (between one year and 12 years) and older infants metabolize several drugs much more rapidly than adults As a result, they require large mg/Kg doses in comparison to adults; for example, theophylline.
In very elderly persons, the liver size is reduced, the microsomal enzyme activity is decreased and hepatic blood flow also declines as a result of reduced cardiac output all of which contribute to decreased metabolism of drugs.
Diet:
The enzyme content and activity is modified by a number of dietary components.
Low protein diet decreases and high protein diet increases the drug metabolizing ability.
This is because the enzyme synthesis is promoted by protein diet which also raises the level of amino acids for conjugation with drugs.
Fat free diet depresses cytochrome P-450 levels since phospholipids, which are important components of microsomes, become deficient.
Dietary deficiency of vitamins (e.g. vitamin A, B2, B3, C and E) and minerals such as Fe, Ca, Mg, Cu and Zn retard the metabolic activity of enzymes.
Grapefruit inhibits metabolism of many drugs and improves their oral availability.
Malnutrition in women results in enhanced metabolism of sex hormones.
Alcohol ingestion results in a short-term decrease followed by an increase in the enzyme activity.
Diseased States:
Liver is the major site for metabolism of most drugs, all disease conditions associated with it result in enhanced half-lives of almost all drugs.
Thus, a reduction in hepatic drug metabolizing ability is apparent in conditions such as hepatic carcinoma, hepatitis, cirrhosis, obstructive jaundice, etc.
Biotransformations such as glycine conjugation of salicylates, oxidation of vitamin D and hydrolysis of procaine which occur in the kidney, are impaired in renal diseases.
Congestive cardiac failure and myocardial infarction which result in a decrease in the blood flow to the liver, impair metabolism of drugs having high hepatic extraction ratio e.g. propranolol and lidocaine.
In diabetes, glucuronidation is reduced due to decreased availability of UDPGA.
4) Altered physiological factors:
Pregnancy
Hormonal imbalance
Disease states
Pregnancy:
Studies in animals have shown that the maternal drug metabolizing ability (of both phase I and phase II reactions) is reduced during the later stages of pregnancy.
This was suggested as due to high levels of steroid hormones in circulation during pregnancy.
Hormonal imbalance:
Higher levels of one hormone may inhibit the activity of few enzymes while inducing that of others.
e.g. Stress related changes in ACTH levels also influence drug biotransformation.
5) Temporal factors:
Circadian rhythm
Circadian rhythm:
Variations in the enzyme activity with light cycle are called as circadian rhythm in drug metabolism.
It has been observed that the enzyme activity is maximum during early morning (6 to 9 a.m.) and minimum in late afternoon (2 to 5 p.m.) which was suggested to correspond with the high and low serum levels of corticosterone.
The study of variations in drug response as influenced by time is called chronopharmacology.
Time dependent change in drug kinetics is known as chronokinetics.
Commonly Asked Question.
Discuss different factors affecting drug biotransformation.