The liver is by far the most important drug metabolising organ, although a number of tissues, including the kidney, gut mucosa, lung and skin also contribute. It is useful to think of drug metabolism in two broad phases:
Phase 1 metabolism brings about a change in the drug molecule by oxidation, reduction or hydrolysis and often introduces a chemically active site into it. The new metabolite may retain biological activity but have different pharmacokinetic properties, e.g. a shorter t1/,.
The most important single group of reactions is the oxidations, in particular those undertaken by the so-called mixed-function (microsomal) oxidases which, as the name indicates, are capable of metabolising a wide variety of compounds. The most important enzyme is a haem protein, cytochrome P450, which takes part in a process whereby molecular oxygen is bound and incorporated into the drug molecule, so forming a new hydroxyl group.
The many forms of cytochrome P450 enzymes (called isoenzymes19) are grouped into families denoted by the letters CYP (from cytochrome P450) followed by numerals. The majority of enzymes concerned with human metabolism belong to familes CYP1,2 and 3. Within these families, are subdivisions denoted by a capital letter followed by a numeral. The family CYP3A is numerically the most important, being involved in the biotransformation of the majority of all drugs; indeed CYP3A4 is expressed outside the liver and may be an important factor that explains poor oral availability of many drugs. Over 100 drugs are known substrates for CYP2D6, > 60 for CYP2C9 and > 50 for CYP2C19.20 Another isoenzyme CYP 2E1, catalyses a reaction involved in the metabolism of alcohol, paracetamol, oestradiol and ethynyloestradiol.
In all there may be as many as 200 separate P450 isoenzymes and this is why we do not need to possess new enzymes for every existing or yet-to-be synthesised drug. Each enzyme is encoded by a separate gene and variation in these genes leads to differences between individuals, and sometimes between ethnic groups, in the ability to metabolise drugs. Persons characterised by polymorphisms (see p. 122) inherit diminished ability to metabolise substrate drugs and if inactivation is dependent on the particular isoenzyme, toxicity may result when these drugs accumulate.
19 An isoenzyme is one of a group of enzmes that catalyse the same reaction but differ in protein structure.
20 Wolf C R, Smith G, Smith R L 2000 Pharmacogenetics. British Medical Journal 320:987-990.
Phase I oxidation of some drugs results in the formation of epoxides which are short-lived and highly reactive metabolites. Epoxides are important because they can bind irreversibly through covalent bonds to cell constituents; indeed, this is one of the principal ways in which drugs are toxic to body tissues. Glutathione is a tripeptide that combines with epoxides, rendering them inactive, and its presence in the liver is part of an important defence machanism against hepatic damage by halothane and paracetamol.
Phase II metabolism involves union of the drug with one of several polar (water-soluble) endogenous molecules that are products of intermediary metabolism, to form a water-soluble conjugate which is readily eliminated by the kidney or, if the molecular weight exceeds 300, in the bile. Morphine, paracetamol and salicylates form conjugates with glucuronic acid (derived from glucose); oral contraceptive steroids form sulphates; isoniazid, phenelzine and dapsone are acetylated. Conjugation with a more polar molecule is also a mechanism by which natural substances are eliminated, e.g. bilirubin as glucuronide, oestrogens as sulphates. Phase II metabolism almost invariably terminates bilogical activity.
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