VARIATIONS IN DRUG-METABOLISM DUE TO GENETIC-POLYMORPHISM - A REVIEW OF THE DEBRISOQUINE SPARTEINE TYPE

Many genes which encode the enzymes responsible for drug metabolism show polymorphism, existing in different forms as a result of mutation. Some polymorphisms are trivial and the resulting enzyme is functionally and even structurally normal; others produce functionally abnormal or inactive enzymes. In this case, affected individuals may have an impaired ability to metabolise those drugs and toxic substances which require that enzyme to be eliminated from the body. Although polymorphisms of particular metabolic routes, e.g. hydrolysis and acetylation, had been known for some time, it was the discovery of those affecting oxidation pathways that brought a new dimension to the relevance of genetic polymorphism in drug metabolism. The most extensively studied is that regulating the oxidative metabolism of the antihypertensive drug debrisoquine, which is caused by the absence in the liver of a specific cytochrome P450 isozyme, P450IID6. More than 25 drugs. including antiarrhythmic agents and tricyclic antidepressants, are substrates of P450IID6, and their metabolism is affected by the debrisoquine oxidation polymorphism. As a consequence, individuals with this metabolic defect experience exaggerated pharmacological responses and adverse reactions when they are treated with standard dosages of these drugs. This polymorphism has also been considered a possible risk factor in certain human diseases, such as bladder and gastrointestinal tract cancers. However, the establishment of a relationship between the metabolism of a drug and the debrisoquine oxidation polymorphism should not lead to a discontinuation of its development or to its withdrawal from clinical use.