Journal article
Midazolam and triazolam biotransformation in mouse and human liver microsomes: relative contribution of CYP3A and CYP2C isoforms
The Journal of pharmacology and experimental therapeutics, Vol.292(2), pp.618-628
02/2000
Handle:
https://hdl.handle.net/2376/108686
PMID: 10640299
Abstract
Midazolam (MDZ) and triazolam (TRZ) hydroxylation, reactions considered to be cytochrome P-4503A (CYP3A)-mediated in humans, were examined in mouse and human liver microsomes. In both species, alpha- and 4-hydroxy metabolites were the principal products. Western blotting with anti-CYP3A1 antibody detected a single band of immunoreactive protein in both human and mouse samples: 0.45 +/- 0. 12 and 2.02 +/- 0.24 pmol/mg protein (mean +/- S.E., n = 3), respectively. Ketoconazole potently inhibited MDZ and TRZ metabolite formation in human liver microsomes (IC(50) range, 0.038-0.049 microM). Ketoconazole also inhibited the formation of both TRZ metabolites and of 4-OH-MDZ formation in mouse liver microsomes (IC(50) range, 0.0076-0.025 microM). However, ketoconazole (10 microM) did not produce 50% inhibition of alpha-OH-MDZ formation in mouse liver microsomes. Anti-CYP3A1 antibodies produced concentration-dependent inhibition of MDZ and TRZ metabolite formation in human liver microsomes and of TRZ metabolite and 4-OH-MDZ formation in mouse liver microsomes to less than 20% of control values but reduced alpha-OH-MDZ formation to only 66% of control values in mouse liver microsomes. Anti-CYP2C11 antibodies inhibited alpha-OH-MDZ metabolite formation in a concentration-dependent manner to 58% of control values in mouse liver microsomes but did not inhibit 4-OH-MDZ formation. Thus, TRZ hydroxylation appears to be CYP3A specific in mice and humans. alpha-Hydroxylation of MDZ has a major CYP2C component in addition to CYP3A in mice, demonstrating that metabolic profiles of drugs in animals cannot be assumed to reflect human metabolic patterns, even with closely related substrates.
Metrics
7 Record Views
Details
- Title
- Midazolam and triazolam biotransformation in mouse and human liver microsomes: relative contribution of CYP3A and CYP2C isoforms
- Creators
- M D Perloff - Department of Pharmacology, Tufts University School of Medicine, Boston, Massachusetts, USAL L von MoltkeM H CourtT KotegawaR I ShaderD J Greenblatt
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.292(2), pp.618-628
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- United States
- Grant note
- MH19924 / NIMH NIH HHS MH34223 / NIMH NIH HHS MH01237 / NIMH NIH HHS
- Identifiers
- 99900546733801842
- Language
- English
- Resource Type
- Journal article