LBOVI-B-3Assessing the role of ethnicity on cytochrome P450 enzymes: A global/Asian study

Abstract

BACKGROUND/AIMS A key consideration for global drug development involves the acceptability of foreign clinical data. Inter-subject/inter-ethnic variability has been attributable to extrinsic and intrinsic factors. Clarifying this relationship by PK and pharmacogenomic (PGx) approaches could enhance global drug development and the acceptability of foreign data in different regions. A six-drug cocktail was used to compare metabolic capacities (MC) of major cytochrome P450 (CYP) enzymes and establish genotype/phenotype associations among Caucasian (C), Chinese (Ch), Korean (K) and Japanese (J) (native, 1st and 3rd generation J) (n=100/group). METHODS Midazolam, caffeine, omeprazole, dextromethorphan, chlorzoxazone, and losartan were used to assess CYP3A4, 1A2, 2C19, 2D6, 2E1, and 2C9, respectively. PGx analyses were conducted and polymorphic loci for each CYP was evaluated. RESULTS Mean MC among the J generations was similar for all six CYP enzymes. Mean MC among the four ethnicities was similar except for lower 2C19 activity in Asians. Mean CYP allelic frequencies for native J were not different from 1st and 3rd generation J, K, and Ch populations but did differ from C at 13 loci. CONCLUSIONS (1) genotype impacted phenotype for CYP2C9, 2C19, and 2D6, (2) genotype had no apparent effects on the observed phenotypes for 1A2, 2E1 and 3A4/5, (3) identical genotypes had similar MC and were independent of ethnicity, and (4) lifestyle factors had negligible effect on genotype/phenotype correlations. Clinical Pharmacology & Therapeutics (2005) 79, P82–P82; doi: 10.1016/j.clpt.2005.12.295