GENETICALLY-DETERMINED ADVERSE DRUG-REACTIONS INVOLVING METABOLISM

Genetic factors represent an important source of interindividual varia tion in drug response. Relatively few adverse drug effects with a phar macodynamic basis are known, and most of the well characterised inheri ted traits take the form of genetic polymorphisms of drug metabolism. Monogenic control of N-acetylation. S-methylation and cytochrome P450- catalysed oxidation of drugs can have important clinical consequences. Individuals who inherit an impaired ability to perform one or more of these reactions may be at an increased risk of concentration-related toxicity. There is a strong case for phenotyping before starting treat ment with a small number of drugs that are polymorphically N-acetylate d or S-methylated. However, the issue of clinical significance is perh aps most relevant for the debrisoquine oxidation polymorphism, which i s mediated by cytochrome CYP2D6 and which determines the pharmacokinet ics of many commonly used drugs. Phenotypic poor metabolisers of debri soquine (8% of Caucasian populations) taking standard doses of some tr icyclic antidepressants, neuroleptics or antiarrhythmic drugs may be p articularly prone to adverse reactions. Similarly, clinically relevant drug interactions between these drugs and other substrates of cytochr ome CYP2D6 may occur in the majority of the population who are extensi ve metabolisers. However, it is clear that in the majority of cases th ere is a need for controlled prospective studies to determine clinical significance. Accordingly, routine debrisoquine phenotyping or geno-t yping before beginning drug treatment is difficult to justify at prese nt, although it may be helpful in individual cases. When prescribing d rugs whose metabolism is polymorphic alone or in combination, careful titration of the dose in both phenotypic groups is prudent. In some ca ses it will be preferable to use alternative therapy to avoid the risk of adverse drug reactions.