Tags

Type your tag names separated by a space and hit enter

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.
Drug Metab Dispos. 1999 Aug; 27(8):902-8.DM

Abstract

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 K(m) and V(max) values for the metabolism of ABT-378 by human liver microsomes were 6.8 +/- 3.6 microM and 9.4 +/- 5.5 nmol of ABT-378 metabolized/mg protein/min, respectively. Ritonavir inhibited human liver microsomal metabolism of ABT-378 potently (K(i) = 0.013 microM). 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 (IC(50) = 1.1 and 4.6 microM), albeit less potently than ritonavir (IC(50) = 0.14 microM). 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 (IC(50) = >30 microM), CYP2C9 (IC(50) = 13.7 and 23.0 microM), CYP2C19 (IC(50) = 28.7 and 38.0 microM), and CYP2D6 (IC(50) = 13.5 and 29.0 microM) were marginal and are not likely to produce clinically significant drug-drug interactions.

Authors+Show Affiliations

Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10421617

Citation

Kumar, G N., et al. "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." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 27, no. 8, 1999, pp. 902-8.
Kumar GN, Dykstra J, Roberts EM, et al. 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. Drug Metab Dispos. 1999;27(8):902-8.
Kumar, G. N., Dykstra, J., Roberts, E. M., Jayanti, V. K., Hickman, D., Uchic, J., Yao, Y., Surber, B., Thomas, S., & Granneman, G. R. (1999). 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. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 27(8), 902-8.
Kumar GN, et al. 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. Drug Metab Dispos. 1999;27(8):902-8. PubMed PMID: 10421617.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR 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. AU - Kumar,G N, AU - Dykstra,J, AU - Roberts,E M, AU - Jayanti,V K, AU - Hickman,D, AU - Uchic,J, AU - Yao,Y, AU - Surber,B, AU - Thomas,S, AU - Granneman,G R, PY - 1999/7/27/pubmed PY - 1999/7/27/medline PY - 1999/7/27/entrez SP - 902 EP - 8 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 27 IS - 8 N2 - 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 K(m) and V(max) values for the metabolism of ABT-378 by human liver microsomes were 6.8 +/- 3.6 microM and 9.4 +/- 5.5 nmol of ABT-378 metabolized/mg protein/min, respectively. Ritonavir inhibited human liver microsomal metabolism of ABT-378 potently (K(i) = 0.013 microM). 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 (IC(50) = 1.1 and 4.6 microM), albeit less potently than ritonavir (IC(50) = 0.14 microM). 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 (IC(50) = >30 microM), CYP2C9 (IC(50) = 13.7 and 23.0 microM), CYP2C19 (IC(50) = 28.7 and 38.0 microM), and CYP2D6 (IC(50) = 13.5 and 29.0 microM) were marginal and are not likely to produce clinically significant drug-drug interactions. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/10421617/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_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10421617 DB - PRIME DP - Unbound Medicine ER -