Abstract

Despite several studies suggesting that CYP3A5 expression can influence the extent of hepatic CYP3A-mediated inhibition, a systematic in vitro-in vivo evaluation of this potential clinically important issue has not been reported. Using representative probes from two distinct CYP3A substrate subgroups (midazolam, erythromycin), the inhibitory potency of fluconazole was evaluated in pooled human liver microsomes (HLM) with a low or high specific CYP3A5 content, in recombinant CYP3A enzymes (rCYP3A), and in healthy volunteers lacking or carrying the CYP3A5^*1 allele. Fluconazole was a slightly more potent inhibitor of CYP3A activity in CYP3A5-HLM than in CYP3A5+ HLM with midazolam (K_i of 15 and 25 μM, respectively) but not with erythromycin (IC₅₀ of 70 and 54 μM, respectively). In comparison, fluconazole was a much more potent inhibitor of rCYP3A4 than rCYP3A5 with both midazolam (K_i of 7.7 and 54 μM, respectively) and erythromycin (IC₅₀ of 100 and 350 μM, respectively). As predicted from HLM, with i.v. midazolam, the average (± S.D.) in vivo K_i (K_i,iv) was significantly higher in CYP3A5^*1 carriers (24 ± 17 and 17 ± 8 μM for homozygous and heterozygous groups, respectively) than in noncarriers (13 ± 6 μM) (p = 0.02). With the erythromycin breath test, the average K_i,iv was not different between homozygous CYP3A5^*1 carriers (30 ± 12 μM) and noncarriers (58 ± 53 μM). In conclusion, the effect of CYP3A5 on hepatic CYP3A-mediated inhibitory drug-drug interactions is substrate-dependent, and HLM, rather than rCYP3A, are the preferred in vitro system for predicting these interactions in vivo.