Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro

The effects of five HIV protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) on cytochrome P450 (CYP) 3A4, 3A5 and 3A7 activities were studied in vitro using testosterone 6 beta-hydroxylation in recombinant CYP3A4, CYP3A5 and CYP3A7 enzymes. The protease inhibitors showed differential inhibitory effects on the three CYP3A forms. Ritonavir and saquinavir were non-selective and preferential inhibitors of CYP3A4 and CYP3A5 (K-i 0.03 mu M and 0.6-0.8 mu M for ritonavir and saquinavir, respectively), and weaker inhibitors of CYP3A7 (K-i 0.6 mu M and 1.8 mu M, respectively). Nelfinavir was a potent and non-selective inhibitor of all three CYP3A forms (K-i 0.3-0.4 mu M). Amprenavir and indinavir preferentially inhibited CYP3A4 (K-i 0.1 mu M and 0.2 mu M, respectively), with weaker inhibitory effects on CYP3A5 (K-i 0.5 mu M and 2.2 mu M, respectively) and CYP3A7 (K-i 2.1 mu M and 10.6 mu M, respectively). In conclusion, significant differences exist in the inhibitory potency of protease inhibitors for different CYP3A forms. Ritonavir, nelfinavir, saquinavir and amprenavir seem to be prone to drug-drug interactions by inhibiting both CYP3A4 and CYP3A5. Especially nelfinavir and ritonavir also have a potential to inhibit foetal CYP3A7-mediated drug metabolism and some endogenous pathways that may be crucial to normal foetal development, while indinavir has the lowest potential to inhibit CYP3A5 and CYP3A7.