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Research ArticleArticle

IN VITRO METABOLISM OF MIDAZOLAM, TRIAZOLAM, NIFEDIPINE, AND TESTOSTERONE BY HUMAN LIVER MICROSOMES AND RECOMBINANT CYTOCHROMES P450: ROLE OF CYP3A4 AND CYP3A5

Kiran C. Patki, Lisa L. von Moltke and David J. Greenblatt
Drug Metabolism and Disposition July 2003, 31 (7) 938-944; DOI: https://doi.org/10.1124/dmd.31.7.938
Kiran C. Patki
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Lisa L. von Moltke
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David J. Greenblatt
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Abstract

Midazolam, triazolam (TRZ), testosterone, and nifedipine have all been widely used as probes for in vitro metabolism of CYP3A. We used these four substrates to assess the contributions of CYP3A4 and CYP3A5 to in vitro biotransformation in human liver microsomes (HLMs) and in recombinant enzymes. Recombinant CYP3A4 and CYP3A5 (rCYP3A4 and rCYP3A5) both produced 1-OH and 4-OH metabolites from midazolam and triazolam, 6β-hydroxytestosterone from testosterone, and oxidized nifedipine from nifedipine. Overall, the metabolic activity of CYP3A5 was less than that of CYP3A4. Ketoconazole potently inhibited midazolam, triazolam, testosterone, and nifedipine metabolite formation in HLMs and in rCYP3A4. The inhibitory potency of ketoconazole in rCYP3A5 was about 5- to 19-fold less than rCYP3A4 for all four substrates. In testosterone interaction studies, testosterone inhibited 1-OH-TRZ formation, but significantly activated 4-OH-TRZ formation in HLMs and rCYP3A4 but not in rCYP3A5. Oxidized nifedipine formation was inhibited by testosterone in rCYP3A4. However, in rCYP3A5, testosterone slightly activated oxidized nifedipine formation at lower concentrations, followed by inhibition. Thus, CYP3A4 and CYP3A5 both contribute to midazolam, triazolam, testosterone, and nifedipine biotransformation in HLMs, with CYP3A5 being metabolically less active than CYP3A4 in general. Because the inhibitory potency of ketoconazole in rCYP3A5 is substantially less than in rCYP3A4 and HLMs, CYP3A5 is probably less important than CYP3A4 in drug-drug interactions involving ketoconazole and CYP3A substrates.

Footnotes

  • ↵1 Abbreviations used are: P450, cytochrome P450; MDZ, midazolam; TRZ, triazolam; TST, testosterone; 6β-HST, 6β-hydroxytestosterone; b5, cytochrome b5; rCYP3A4, recombinant CYP3A4; rCYP3A5, recombinant CYP3A5; HLM, human liver microsomes; DDI, drug-drug interaction; HPLC, high-performance liquid chromatography; HRP, horseradish peroxidase; EIC, estimated intrinsic clearance; Ks, uncompetitive substrate inhibition constant; OR, oxidoreductase.

  • Supported by Grants MH-58435, DA-13209, DA-13834, DK-58496, DA-05258, AG-17880, MH-01237, and RR-00054 from the Department of Health and Human Services. K.C.P. is supported by the Tufts-Pfizer Fellowship Program in Clinical Pharmacology.

    • Received July 15, 2002.
    • Accepted March 24, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (7)
Drug Metabolism and Disposition
Vol. 31, Issue 7
1 Jul 2003
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IN VITRO METABOLISM OF MIDAZOLAM, TRIAZOLAM, NIFEDIPINE, AND TESTOSTERONE BY HUMAN LIVER MICROSOMES AND RECOMBINANT CYTOCHROMES P450: ROLE OF CYP3A4 AND CYP3A5
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Research ArticleArticle

IN VITRO METABOLISM OF MIDAZOLAM, TRIAZOLAM, NIFEDIPINE, AND TESTOSTERONE BY HUMAN LIVER MICROSOMES AND RECOMBINANT CYTOCHROMES P450: ROLE OF CYP3A4 AND CYP3A5

Kiran C. Patki, Lisa L. von Moltke and David J. Greenblatt
Drug Metabolism and Disposition July 1, 2003, 31 (7) 938-944; DOI: https://doi.org/10.1124/dmd.31.7.938

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Research ArticleArticle

IN VITRO METABOLISM OF MIDAZOLAM, TRIAZOLAM, NIFEDIPINE, AND TESTOSTERONE BY HUMAN LIVER MICROSOMES AND RECOMBINANT CYTOCHROMES P450: ROLE OF CYP3A4 AND CYP3A5

Kiran C. Patki, Lisa L. von Moltke and David J. Greenblatt
Drug Metabolism and Disposition July 1, 2003, 31 (7) 938-944; DOI: https://doi.org/10.1124/dmd.31.7.938
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