Biosynthesis and Identification of Metabolites of Maraviroc and Their Use in Experiments to Delineate the Relative Contributions of Cytochrome P4503A4 versus 3A5

Maraviroc (MVC) is a CCR5 coreceptor antagonist indicated in combination with other antiretroviral agents for the treatment of CCR5-tropic human immunodefinciency virus-1 infection. In this study, the metabolism of MVC was investigated in human liver microsomes to delineate the relative roles of CYP3A4 and CYP3A5. MVC is metabolized to five hydroxylated metabolites, all of which were biosynthesized and identified using mass and NMR spectroscopy. The sites of metabolism were the 2- and 3-positions of the 4,4-difluorocyclohexyl moiety and the methyl of the triazole moiety. Absolute configurations were ultimately ascertained by comparison to authentic standards. The biosynthesized metabolites were used for quantitative in vitro experiments in liver microsomes using cyp3cide, a selective inactivator of CYP3A4. (1S,2S)-2-OH-MVC was the main metabolite representing approximately half of the total metabolism, and CYP3A5 contributed approximately 40% to that pathway in microsomes from CYP3A5*1/*1 donors. The other four metabolites were almost exclusively metabolized by CYP3A4. (1S,2S)-2-hydroxylation also correlated to T-5 N-oxidation, a CYP3A5-specific activity. These data are consistent with clinical pharmacokinetic data wherein CYP3A5 extensive metabolizer subjects showed a modestly lower exposure to MVC.

[1]  L. Mcfadyen,et al.  Clinical Relevance of CYP3A5 Genotype on Maraviroc Exposures , 2015, Drug Metabolism and Disposition.

[2]  E. Fuchs,et al.  CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers , 2014, Drug Metabolism and Disposition.

[3]  R. Obach,et al.  Relative Contributions of Cytochrome CYP3A4 Versus CYP3A5 for CYP3A-Cleared Drugs Assessed In Vitro Using a CYP3A4-Selective Inactivator (CYP3cide) , 2014, Drug Metabolism and Disposition.

[4]  G. S. Walker,et al.  Characterization of T-5 N-Oxide Formation as the First Highly Selective Measure of CYP3A5 Activity , 2014, Drug Metabolism and Disposition.

[5]  B. Weatherley,et al.  Pharmacokinetics, Safety, and Tolerability of Maraviroc in HIV-Negative Subjects with Impaired Renal Function , 2013, HIV clinical trials.

[6]  C. Hendrix,et al.  Cytochrome P450 3A5 Plays a Prominent Role in the Oxidative Metabolism of the Anti-Human Immunodeficiency Virus Drug Maraviroc , 2012, Drug Metabolism and Disposition.

[7]  G. S. Walker,et al.  Selective Mechanism-Based Inactivation of CYP3A4 by CYP3cide (PF-04981517) and Its Utility as an In Vitro Tool for Delineating the Relative Roles of CYP3A4 versus CYP3A5 in the Metabolism of Drugs , 2012, Drug Metabolism and Disposition.

[8]  Russ B Altman,et al.  PharmGKB summary: very important pharmacogene information for CYP3A5. , 2012, Pharmacogenetics and genomics.

[9]  Yuan Chen,et al.  Utility of Intersystem Extrapolation Factors in Early Reaction Phenotyping and the Quantitative Extrapolation of Human Liver Microsomal Intrinsic Clearance Using Recombinant Cytochromes P450 , 2011, Drug Metabolism and Disposition.

[10]  D. Back,et al.  Maraviroc: Pharmacokinetics and drug Interactions , 2009 .

[11]  Maurice Dickins,et al.  Maraviroc: in vitro assessment of drug-drug interaction potential. , 2008, British journal of clinical pharmacology.

[12]  Angus N R Nedderman,et al.  Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects. , 2008, British journal of clinical pharmacology.

[13]  David A. Price,et al.  Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity , 2005, Antimicrobial Agents and Chemotherapy.

[14]  Michel Roger,et al.  CYP3A5 GENETIC POLYMORPHISMS IN DIFFERENT ETHNIC POPULATIONS , 2005, Drug Metabolism and Disposition.

[15]  C. Ernest,et al.  Mechanism-Based Inactivation of CYP3A by HIV Protease Inhibitors , 2005, Journal of Pharmacology and Experimental Therapeutics.

[16]  G. Tucker,et al.  Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors , 2004, Xenobiotica; the fate of foreign compounds in biological systems.

[17]  S. Philpott.  HIV-1 coreceptor usage, transmission, and disease progression. , 2003, Current HIV research.

[18]  J. Mascola,et al.  The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression , 1997, Nature Medicine.

[19]  O. Toupance,et al.  Interindividual variability in the concentration-effect relationship of antilymphocyte globulins - a possible influence of FcgammaRIIIa genetic polymorphism. , 2008, British journal of clinical pharmacology.

[20]  P. Neuvonen,et al.  Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro. , 2006, Basic & clinical pharmacology & toxicology.