Polymorphic differences in drug metabolism and response.

Abstract

Genetic differences in drug metabolism and response, also referred to as pharmacogenetic differences, result in polymorphism in the pharmacokinetics and pharmacodynamics of a drug. Acetylation and debrisoquin oxidation have been extensively studied by investigators in order to identify the geographical distribution of these polymorphic differences in drug metabolism. Metabolic pathways for various drugs have been correlated with debrisoquin metabolism, the observed polymorphism being attributed to variants of cytochrome P-450. Medical recognition of these polymorphic differences in drug disposition is vital because of clinical manifestations arising from these differences. Deficiencies in metabolic pathways enhance susceptibility to adverse reactions but reduce the susceptibility to chemical carcinogenesis. Therapeutic success or failure may result from concomitant administration of drugs that undergo metabolism via pathways with co-regulated genetic polymorphism and is, therefore, an important consideration in the treatment of any population of varying ethnic proportions. Anomalous metabolism and response to a drug should be investigated with innocuous probes, e.g., dextromethorphan or antipyrine at low doses, and if possible, correlated to metabolic pathways that have been previously identified as demonstrating genetic polymorphism.