Pharmacogenetic aspects of biological variability

Abstract

ABSTRACTIn the field of pharmacogenetics, new insights have been obtained over the past few years with respect to hepatic hydroxylation and acetylation of drugs. Metabolic defects within the particular enzyme systems can be accompanied by multiple consequences, such as altered pharmacokinetics and unexpected side‐effects of drugs.In Caucasian populations, the genetic defect of hydroxylation of debrisoquine occurs in approximately 9% of the population. The mephenytoin‐type drug hydroxylation defect, resulting from another hydroxylation polymorphism, can be demonstrated in 5% and 18% of Caucasian and Asian population samples, respectively. Such interindividual (phenotypic) differences of oxidative drug elimination can be detected after the peroral administration of a single dose of debrisoquine and mephenytoin followed by an 8 h urine collection. In hydroxylation‐deficient subjects, dose‐dependent drug toxicities occur after chronic drug administration of β‐blockers, antidepressants, perhexiline, phenacetine and others.With respect to the acetylation polymorphism, rapid and slow acetylator phenotypes exhibit approximately a 1: 1 distribution in Caucasian populations. That particular phenotype can be determined in plasma or urine after peroral administration of 500 mg sulfadimidine. A new test for the assessment of polymorphic acetylation has recently become available in the form of acetylamino‐formylamino‐methyluracil analysis in urine after peroral administration of caffeine. The clinical consequences of the inherited rapid and slow acetylation capacity of the liver are primarily relevant for slow acetylator phenotypes, because side‐effects of isoniazid, salazopyrine, hydralazine and procainamide occur more frequently in this condition.Pharmacogenetics and ecogenetics are two closely related entities. It might therefore be speculated that pharmacogenetically determined predispositions will also influence the metabolism of as yet unknown endo‐ and xenobiotic substances. Their varying abundances, for