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P450 3A5 is primarily responsible for the formation of the most abundant oxidative metabolite of maraviroc
Author(s) -
Lu Yanhui,
Hendrix Craig W.,
Bumpus Namandjé N.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1052.2
Subject(s) - maraviroc , metabolite , cyp3a4 , microsome , chemistry , pharmacology , cytochrome p450 , biochemistry , metabolism , biology , enzyme , virology , human immunodeficiency virus (hiv)
Maraviroc is an anti‐HIV drug that acts by blocking viral entry into target cells. Although maraviroc is known to be metabolized by the cytochromes P450 (CYP) to several products, a comprehensive analysis of the enzymes involved has yet to be reported; therefore, this work sought to identify the CYPs involved in the oxidative metabolism of maraviroc. Using a panel of cDNA‐expressed CYPs it was determined that the major oxidative metabolite of maraviroc (detected using liquid chromatography‐mass spectrometry) was primarily formed by CYP3A5. Tandem mass spectrometry analysis indicated that the CYP3A5‐mediated oxygen insertion occurred on the difluorocyclohexane ring of maraviroc. For this reaction, the V max for CYP3A4 and CYP3A5 was 0.04 and 0.93 pmole/min/pmole P450, respectively. In addition, the K m values were 11.1 μM and 48.9 μM, respectively. Human liver microsomes isolated from donors homozygous for the CYP3A5*3 allele, which results in low expression of CYP3A5, exhibited a 79% decrease in formation of this metabolite as compared to production by human liver microsomes isolated from donors homozygous for the CYP3A5*1 allele. In conclusion, the major oxidative metabolite of maraviroc was found to be formed primarily by CYP3A5. These results indicate that maraviroc may be used as a tool to distinguish the activity of CYP3A5 from that of CYP3A4. Support: PhRMA Foundation Research Starter Grant to N.B.