Genetic polymorphisms of the CYP3A5 and MDR-1 genes and effect of clarithromycin (CLAR) on midazolam (MDZ) pharmacokinetics

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