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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.

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.

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  • Authors+Show Affiliations

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    Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.

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    Source

    MeSH

    Antibodies, Blocking
    Aryl Hydrocarbon Hydroxylases
    Chromatography, High Pressure Liquid
    Cytochrome P-450 CYP3A
    Cytochrome P-450 Enzyme Inhibitors
    Cytochrome P-450 Enzyme System
    Drug Interactions
    HIV Protease Inhibitors
    Humans
    In Vitro Techniques
    Isoenzymes
    Kinetics
    Lopinavir
    Microsomes, Liver
    Oxidoreductases, N-Demethylating
    Pyrimidinones
    Ritonavir

    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., ... 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), pp. 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 -