[Clinically significant inherited differences in the mode of action of drugs]

An important source of interindividual differences in drug action are inherited differences in the pharmacokinetics and pharmacodynamics of many drugs. For most enzymatic reactions of drug biotransformation in the liver, genetic polymorphisms have been observed which lead to a decreased rate of metabolism and/or a different pattern of metabolites in certain subpopulations, ethnic groups or families. Examples of frequent polymorphisms in drug-metabolizing enzymes are deficient N-acetyltransferase (50-70% of the population) and deficient debrisoquine hydroxylase (10% of the population). "Slow acetylators" inactivate isoniazid, hydralazine, procainamide, phenelzine, dapsone, sulfamethazine (sulfadimidine), sulfapyridine and nitrazepam at a decreased rate. The molecular genetic defect causing deficient debrisoquine hydroxylation is still unclear and also affects the metabolism of phenytoin, phenacetin, guanoxan, sparteine, methoxyamphetamine, nortriptyline, encainide, perhexiline and probably other drugs. A relationship has been observed between the defect of metabolism and the clinical effects and toxicity of the drugs involved.