Variability in human drug metabolism and its implications

Abstract

Apart from the well known factors involved in drug absorption, distribution and renal excretion, the major cause for interindividual differences in the kinetics of drugs in man is the variability in drug metabolizing activity. A critical review of the influence of genetic factors, age, sex, smoking, alcohol, diet, liver disease and thyroid disease is undertaken. Additionally, drugs causing microsomal induction or inhibition and the effect of exposure to chemicals must be known at a relatively early stage in new drug development. "First-pass" hepatic effect and enzyme saturation are respectively responsible for the wide range of plasma concentrations of some highly liver-extracted drugs or for non-linear kinetics. The implications of variability in human drug metabolism are discussed for drug therapy in daily practice and for new drugs under development. It can be concluded that a high degree of interrelationships between genetic and environmental factors exists in the case of most drugs and that many drugs require dose individualization during actual therapy.