One of the biggest problems encountered in therapeutics is the extreme variability that exists in the response to drugs. While factors such as age, sex, obesity, renal and liver disease have accounted for some of this variability it is becoming increasingly clear that ethnic background pharmacogenetic makeup are also very important contributors. Enzymes that are primarily involved in the metabolism of drugs may exhibit different activities or may occur in different amounts among populations of diverse ethnic backgrounds. Thus differences in response to drugs could be attributed, in part to the existence of drug metabolizing enzyme polymorphisms; in particular, those enzymes responsible for the acetylation, oxidation, hydroxylation, and methylation of drugs. The frequency of many of these polymorphisms have not been identified for many ethnic populations. It is therefore the intention of this proposal to determine the occurrence of dapsone acetylation, debrisoquine hydroxylation, mephenytoin hydroxylation, thiopurine-S-methylation and catechol-O-methylation polymorphisms in the Black American, Haitian, and Seminole Indian populations of South Florida. Subjects from these ethnic groups will receive the above probe drugs and blood and urine samples will be analyzed for parent drug and metabolites. The individual polymorphisms will be determined based on the extent of metabolism of these test drugs. Thiopurine and catechol methylation polymorphisms will be determined by measuring the respective blood cell methyltransferase enzyme activities.
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