The study of differences in the disposition and responsiveness of drugs on the basis of racial/ethnic origin is a relatively neglected area of investigation. The increasing diversity of the U.S. population and the worldwide nature of drug development, evaluation and licensing, however, make this factor one of increasing importance and relevance. A series of studies will focus on the polymorphically distributed enzyme responsible for the 4'-hydroxylation of mephenytoin (P450IICMP), since it is hypothesized that substrate specificity may be different between Chinese and Caucasian subjects. Accordingly, it is planned to determine whether inter-racial differences in disposition exist with known P450IICMP substrates, such as hexobarbital, omeprazole and proguanil. The effects of liver disease on these drugs will also be determined. Another enzyme of interest is P450IIIA4, which is involved in the metabolism of a large number of diverse drugs and environmental agents. Studies will be performed to determine the validity of the N-oxidation of dapsone as an in vivo probe for P450IIIA4 catalytic activity. Subsequently, the distribution of such activity will be determined in various populations of different racial origin - Caucasians, Blacks, Chinese and Indians. The pharmacokinetic and pharmacodynamic significance of differences in P450IIIA4 activity will be established by studies with the widely used hypnotic triazolam (Halcion). This will involve comparative study of the benzodiazepine's disposition and central nervous system effects in individuals at the two extremes of the population distribution of P450IIIA4 activity. Studies in different racial groups will also be performed. The relationship between interindividual differences in P450IIIA4 activity and the ability of macrolide antibiotics, such as erythromycin, to inhibit triazolam's metabolism and to change its effects will also be examined. Finally, it is proposed to investigate the role of P450IIIA4 in the metabolism of the non-sedating antihistamine terfenadine (Seldane). The disposition of terfenadine and its active carboxylic acid metabolite will be defined in relationship to P450IIIA4 activity, including the effects of drug:drug interactions produced by inhibition of such metabolism.
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