Abstract

Objective CLAR significantly reduces the intravenous and oral clearance of MDZ. In this study, we investigate the possible role of the CYP3A5 and MDR-1 gene variants in this drug-drug interaction. Methods A retrospective analysis was done in 24 healthy volunteers who had received simultaneous administration of IV and oral MDZ before and after 7 days CLAR. CYP3A5*3 and MDR-1 G2677T alleles were determined by PCR. Results Five subjects had a CYP3A5*1 allele including one subject with a CYP3A5*1/*1 genotype. The baseline systemic clearance (31.1 ± 9.1 vs 30.4 ± 9.3 L/hr, p = 0.9) and oral clearance (165.4 ± 91.1 vs 113.8 ± 80.5 L/hr, p =0.2) of MDZ did not differ between CYP3A5 *1 and *3/*3 carriers, respectively. After CLAR treatment, there were no statistical significant differences in systemic clearance (17.2 ± 10.7 vs 10.9 ± 5.4 L/hr, p = 0.07) and percent change in oral clearance (74% vs 83%, p = 0.1) of MDZ between CYP3A5 *1 and *3/*3 carriers, respectively; however, oral clearance (49.6 ± 63.1 vs 15.0 ± 8.3 L/hr, p = 0.02) of MDZ and percent change in systemic clearance (45% vs 63%, p = 0.04) in CYP3A5*1 carriers were significantly higher than *3/*3 homozygotes. No difference in pharmacokinetics or extent of drug interaction was found between the MDR-1 genotypes. Conclusion These data suggest that people who possess a CYP3A5*1 allele are less susceptible to CYP3A inhibition by CLAR. Clinical Pharmacology & Therapeutics (2004) 75, P70–P70; doi: 10.1016/j.clpt.2003.11.264

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