Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: A positive drug-drug interaction

ABT-378 is a potent in vitro inhibitor of the HIV protease and is currently being developed for coadministration with another HIV protease inhibitor, ritonavir, as an oral therapeutic treatment for HIV infection. In the prese nt study, the effect of ritonavir, a potent inhibitor of cytochrome P-450 ( CYP) 3A, on the in vitro metabolism of ABT-378 was examined. Furthermore, t he effect of ABT-378-ritonavir combinations on several CYP-dependent monoox ygenase activities in human liver microsomes was also examined. ABT-378 was found to undergo NADPH- and CYP3A4/5-dependent metabolism to three major m etabolites, M-1 (4-oxo) and M-3/M-4 (4-hydroxy epimers), as well as several minor oxidative metabolites in human liver microsomes. The mean apparent K -m and V-max values for the metabolism of ABT-378 by human liver microsomes were 6.8 +/- 3.6 mu M and 9.4 +/- 5.5 nmol of ABT-378 metabolized/mg prote in/min, respectively. Ritonavir inhibited human liver microsomal metabolism of ABT-378 potently (K-i = 0.013 mu M). The combination of ABT-378 and rit onavir was much weaker in inhibiting CYP-mediated biotransformations than r itonavir alone, and the inhibitory effect appears to be primarily due to th e ritonavir component of the combination. The ABT-378-ritonavir combination s (at 3:1 and 29:1 ratios) inhibited CYP3A (IC50 = 1.1 and 4.6 mu M), albei t less potently than ritonavir (IC50 = 0.14 mu M). Metabolic reactions medi ated by CYP1A2, CYP2A6, and CYP2E1 were not affected by the ABT-378-ritonav ir combinations, The inhibitory effects of ABT-378-ritonavir combinations o n CYP2B6 (IC50 = >30 mu M), CYP2C9 (IC50 = 13.7 and 23.0 mu M), CYP2C19 (IC 50 = 28.7 and 38.0 mu M), and CYP2D6 (IC50 = 13.5 and 29.0 mu M) were margi nal and are not likely to produce clinically significant drug-drug interact ions.