In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5.
Article Details
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Patki KC, Von Moltke LL, Greenblatt DJ
In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5.
Drug Metab Dispos. 2003 Jul;31(7):938-44.
- PubMed ID
- 12814972 [ View in PubMed]
- 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, 6 beta-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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Midazolam Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails Nifedipine Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails Testosterone cypionate Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorInducerDetails Testosterone cypionate Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails Testosterone enanthate Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorInducerDetails Testosterone enanthate Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails Testosterone undecanoate Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorInducerDetails Testosterone undecanoate Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails Triazolam Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareFelodipineVoriconazole The serum concentration of Felodipine can be increased when it is combined with Voriconazole. IsradipineVoriconazole The serum concentration of Isradipine can be increased when it is combined with Voriconazole. NicardipineVoriconazole The serum concentration of Nicardipine can be increased when it is combined with Voriconazole. NifedipineVoriconazole The serum concentration of Nifedipine can be increased when it is combined with Voriconazole. NimodipineVoriconazole The serum concentration of Nimodipine can be increased when it is combined with Voriconazole. NisoldipineVoriconazole The serum concentration of Nisoldipine can be increased when it is combined with Voriconazole. 
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