Clinical consequences of polymorphic drug oxidation

Abstract

Many characters are genetically regulated as polymorphisms. This means that discrete groups are seen within the distribution of a certain character. Drug metabolism is no exception and the polymorphism of acetylation is recognised since the 50's. Polymorphic drug oxidation was discovered in the 70's and has been extensively studied. There are two fully established polymorphisms in drug oxidation named as the debrisoquine/sparteine and the s-mephenytoin hydroxylation polymorphisms. The metabolism of a number of important drugs cosegregates with that of debrisoquine. Among these drugs are beta-blockers, antiarrhythmics, tricyclic antidepressants and neuroleptics. Apart from accumulation of parent drug and active metabolite, also reduced formation of active metabolite occur for some drugs in slow metabolisers. There are, however, few cases where the presence of polymorphic drug metabolism is of significant disadvantage. The polymorphisms will add to variability in drug clearance but the potential clinical importance should be evaluated for each drug. The cytochrome P-450 isozyme responsible for debrisoquine hydroxylation is of high affinity-low capacity character, which means that it can be saturated under certain circumstances. This will decrease the difference in drug metabolic rate between rapid and low metabolisers as will inhibitors of the debrisoquine isozyme like cimetidine, quinidine and propafenone. The debrisoquine isozyme is not readily inducible. In cases where a major metabolic route or the formation of an active metabolite are polymorphically controlled, knowledge about a patient's oxidator status might be of practical value for dose adjustments especially if there is a narrow therapeutic ratio or an established concentration-effect relationship. For some drugs it is difficult to differentiate between insufficient therapeutic effect and symptoms of overdosage. Tricyclic antidepressants and neuroleptics meet some of these criteria and patients who get recurrent treatment may benefit if the physician has knowledge about debrisoquine metabolic phenotype. Otherwise, the clinical consequences of polymorphisms in drug oxidation seem so far to be limited, considering that a number of disease conditions have not shown any clear association with oxidation status. The polymorphisms in drug metabolism should be considered as a part of natural variability which could in fact be larger with other drugs that do not show polymorphic elimination.