RT Journal Article
SR Electronic
T1 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
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 902
OP 908
VO 27
IS 8
A1 Kumar, Gondi N.
A1 Dykstra, Jennifer
A1 Roberts, Ellen M.
A1 Jayanti, Venkata K.
A1 Hickman, Dean
A1 Uchic, John
A1 Yao, Ye
A1 Surber, Bruce
A1 Thomas, Samuel
A1 Granneman, G. Richard
YR 1999
UL http://dmd.aspetjournals.org/content/27/8/902.abstract
AB 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 present 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, the effect of ABT-378-ritonavir combinations on several CYP-dependent monooxygenase activities in human liver microsomes was also examined. ABT-378 was found to undergo NADPH- and CYP3A4/5-dependent metabolism to three major metabolites, 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 Km andVmax values for the metabolism of ABT-378 by human liver microsomes were 6.8 ± 3.6 μM and 9.4 ± 5.5 nmol of ABT-378 metabolized/mg protein/min, respectively. Ritonavir inhibited human liver microsomal metabolism of ABT-378 potently (Ki = 0.013 μM). The combination of ABT-378 and ritonavir was much weaker in inhibiting CYP-mediated biotransformations than ritonavir alone, and the inhibitory effect appears to be primarily due to the ritonavir component of the combination. The ABT-378-ritonavir combinations (at 3:1 and 29:1 ratios) inhibited CYP3A (IC50 = 1.1 and 4.6 μM), albeit less potently than ritonavir (IC50 = 0.14 μM). Metabolic reactions mediated by CYP1A2, CYP2A6, and CYP2E1 were not affected by the ABT-378-ritonavir combinations. The inhibitory effects of ABT-378-ritonavir combinations on CYP2B6 (IC50 = >30 μM), CYP2C9 (IC50 = 13.7 and 23.0 μM), CYP2C19 (IC50 = 28.7 and 38.0 μM), and CYP2D6 (IC50 = 13.5 and 29.0 μM) were marginal and are not likely to produce clinically significant drug-drug interactions. The American Society for Pharmacology and Experimental Therapeutics