Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms
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1. The primary metabolism of diazepam was studied in human liver microsomes in order to investigate the kinetics and to identify the cytochrome P450 (CYP) isoforms responsible for the formation of the main diazepam metabolites, temazepam and N‐desmethyldiazepam. 2. The formation kinetics of both metabolites were atypical and consistent with the occurrence of substrate activation. A sigmoid Vmax model equivalent to the Hill equation was used to fit the data. The degree of sigmoidicity was greater for temazepam formation than for N‐ desmethyldiazepam formation, so that the ratio of desmethyldiazepam:temazepam formation increased as the substrate (diazepam) concentration decreased. 3. alpha‐Naphthoflavone activated both reactions but with a greater effect on temazepam formation than on N‐desmethyldiazepam formation. In the presence of 25 microM alpha‐ naphthoflavone the kinetics for both pathways were approximated by Michaelis‐Menten kinetics. 4. Studies with a series of CYP isoform selective inhibitors and with an inhibitory anti‐CYP2C antibody indicated that temazepam formation was carried out mainly by CYP3A isoforms, whereas the formation of N‐desmethyldiazepam was mediated by both CYP3A isoforms and S‐mephenytoin hydroxylase.
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DMD undergoes glucuronidation (25%) and hydroxylation (50%) by CYP2C19 and CYP3A4 to form oxazepam.
“N-Desmethyldiazepam undergoes glucuronidation to form a glucuronide conjugate (25%) and is hydroxylated (50%) by CYP 2C19 and CYP 3A4 to form oxazepam (24,37).”
From Benzodiazepines in epilepsy: Pharmacology and pharmacokinetics (2008) · cites this paper as [37]
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- Authors
- Andersson, T., Miners, J., Veronese, M., & Birkett, D.
- Affiliations
- Flinders Medical Centre (AU)
- ORCID
- Andersson, T
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 1994-08
- Volume
- 38
- Issue
- 2
- Pages
- 131-137
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC1364858
- OpenAlex
- W2028599478
- Cited by
- 225
- References
- 33
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 3 · 2018: 4 · 2017: 4 · 2016: 6 · 2015: 7 · 2014: 9 · 2013: 3 · 2012: 4
- FWCI
- 15.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Clinical Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- diazepam metabolism, temazepam, N-desmethyldiazepam, cytochrome P450, substrate activation, sigmoid kinetics, Hill equation, alpha-naphthoflavone, CYP2C, enzyme kinetics, human liver microsomes
- MeSH terms
- Aryl Hydrocarbon Hydroxylases, Benzoflavones, Cytochrome P-450 Enzyme System, Nordazepam, Diazepam, Humans, Mixed Function Oxygenases, Isoenzymes, Mephenytoin, Microsomes, Liver, Temazepam, Cytochrome P-450 CYP2E1, Cytochrome P-450 CYP2C19, In Vitro Techniques
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