Species, ethnic, and individual differences in human drug-metabolizing cytochrome P450 enzymes

Abstract

Safety testing of drug metabolites resulting from P450 enzyme activity in humans is important for developing drug candidates and investigating the potential for idiosyncratic drug reactions. Drug-induced hepatotoxicity may be caused by active intermediates formed by animal or, more commonly, human cytochrome P450 enzymes from common toxicants or drugs. Safety assessments of drug metabolites are often carried out in minipigs, monkeys, and genetically engineered mouse models that express human enzymes. Consequently, it is important to understand and take into account species differences in the roles of P450 enzymes in drug metabolism. During the past 30 years, a vast amount of research has focused on the substrates of human P450 enzymes and the metabolites formed; however, the issue of human-specific metabolites is complex and much remains to be learned.