Genetic and environmental factors affecting drug disposition in man

Large interindividual variations in drug response can arise from multiple genetic and environmental factors affecting drug absorption, distribution, biotransformation, excretion, interaction with receptor sites, or combinations of these. Twin and family studies disclosed that for several commonly used drugs genetic factors are predominantly responsible for large interindividual variations in drug disposition that occur in normal volunteers under basal conditions. Environmental contributions were surprisingly small. While it has been convenient in such studies to separate genetic from environmental contributions as though they were discrete, unrelated entities, the transcriptional and translational mechanisms by which genetic information is expressed require environmental participation. Conversely, many environmental factors that alter rates of drug disposition do so by affecting genetic mechanisms (for example, phenobarbital induction of human hepatic antipyrine metabolism and benzpyrene induction of aryl hydrocarbon hydroxylase [AHH] activity in cultured human lymphocytes). Environmental chemicals, such as DDT, polychlorinated biphenyls, and polycyclic hydrocarbons, can alter, through induction, basal, genetically controlled hepatic drug‐metabolizing enzyme activity. Disease states can markedly change an individual's basal, genetically controlled rate of drug elimination. Assurance of a truly basal, uninduced, or uninhibited state can never be complete but is partially attainable through repeated measurements of the rate of elimination of a particular drug and through a careful history of exposures at work and at home to potential compounds or conditions that could alter the basal rate of drug elimination. The existence and operation of numerous environmental factors, each with differing capability of altering the basal, genetically controlled level of drug metabolism, make it exceedingly difficult to attribute quantitatively different portions of the total interindividual variation to specific single environmental factors. In this regard, a major problem in man is that most populations are markedly heterogeneous with respect both to environmental and genetic factors that influence drug disposition. The task of partitioning the total interindividual variation in drug elimination of such heterogeneous populations into component parts is further complicated because some seemingly pure “environmental” factors (smoking and diet) are closely associated with other