ArticleDrug metabolism and disposition: the biological fate of chemicals2012
Cytochrome P450 3A5 plays a prominent role in the oxidative metabolism of the anti-human immunodeficiency virus drug maraviroc.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- No Clinical Impact of CYP3A5 Gene Polymorphisms on the Pharmacokinetics and/or Efficacy of Maraviroc in Healthy Volunteers and HIV-1-Infected Subjects.Journal of clinical pharmacology · 2019Trial
- Characterization of CYP3A5 Selective Inhibitors for Reaction Phenotyping of Drug Candidates.The AAPS journal · 2024Article
- Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5.Molecules (Basel, Switzerland) · 2023Article
- Maraviroc Population Pharmacokinetics Within the First 6 Weeks of Life.The Pediatric infectious disease journal · 2022Article
- Identification of Potential Cytochrome P450 3A5 Inhibitors: An Extensive Virtual Screening through Molecular Docking, Negative Image-Based Screening, Machine Learning and Molecular Dynamics Simulation Studies.International journal of molecular sciences · 2022Article
- Unraveling the Structural Basis of Selective Inhibition of Human Cytochrome P450 3A5.Journal of the American Chemical Society · 2021Article
- Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors.Cancer chemotherapy and pharmacology · 2021Article
- Pharmacogenomics of Antiretroviral Drug Metabolism and Transport.Annual review of pharmacology and toxicology · 2021Review
- Tandem mass spectrometry of small-molecule antiviral drugs: 1. HIV-related antivirals.International journal of mass spectrometry · 2020Review
- Interindividual Variation in CYP3A Activity Influences Lapatinib Bioactivation.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Active-site differences between substrate-free and ritonavir-bound cytochrome P450 (CYP) 3A5 reveal plasticity differences between CYP3A5 and CYP3A4.The Journal of biological chemistry · 2019Article
- Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu.Frontiers in pharmacology · 2019Article
- The X-Ray Crystal Structure of the Human Mono-Oxygenase Cytochrome P450 3A5-Ritonavir Complex Reveals Active Site Differences between P450s 3A4 and 3A5.Molecular pharmacology · 2018Article
- Gomisin A is a Novel Isoform-Specific Probe for the Selective Sensing of Human Cytochrome P450 3A4 in Liver Microsomes and Living Cells.The AAPS journal · 2016Article
- Effects of CYP3A5 genetic polymorphism and smoking on the prognosis of non-small-cell lung cancer.OncoTargets and therapy · 2016Article
- Maraviroc: a review of its use in HIV infection and beyond.Drug design, development and therapy · 2015Review
- CYP3A5 genotype impacts maraviroc concentrations in healthy volunteers.Drug metabolism and disposition: the biological fate of chemicals · 2014Article
- Dissimilarities in the metabolism of antiretroviral drugs used in HIV pre-exposure prophylaxis in colon and vagina tissues.Biochemical pharmacology · 2013Article
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3 authors.
Funding
Abstract
Maraviroc is an anti-human immunodeficiency virus drug that acts by blocking viral entry into target cells. With use of ultra-performance liquid chromatography-mass spectrometry several monooxygenated, dioxygenated, and glucuronidated metabolites of maraviroc were identified both in vitro and in vivo. Characterization of the enzymes involved in the production of these metabolites determined that cytochrome P450 3A5 was the principal enzyme responsible for the formation of an abundant metabolite of maraviroc that resulted from oxygenation of the dichlorocyclohexane ring. For the formation of this metabolite, the V(max) values for CYP3A4 and CYP3A5 were 0.04 and 0.93 pmol · min⁻¹ · pmol P450⁻¹, and the K(m) values were 11.1 and 48.9 μM, respectively. Furthermore, human liver microsomes isolated from donors homozygous for the loss-of-function CYP3A5*3 allele exhibited a 79% decrease in formation of this metabolite compared with those homozygous for the wild-type CYP3A5*1 allele. To probe which divergent residues between CYP3A4 and CYP3A5 might play a role in the differential activities of these enzymes toward maraviroc, mutations were introduced into both enzymes and metabolism of maraviroc was measured. A CYP3A5 L57F mutant exhibited a 61% decrease in the formation of this metabolite, whereas formation by a CYP3A4 F57L mutant was increased by 337% compared with that of the wild type. Taken together, these data provide novel insights into the biotransformation of maraviroc as well as the potential role of CYP3A4 and CYP3A5 divergent residues in the enzymatic activities of these two highly homologous enzymes.
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