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Vol. 292, Issue 2, 618-628, February 2000

Midazolam and Triazolam Biotransformation in Mouse and Human Liver Microsomes: Relative Contribution of CYP3A and CYP2C Isoforms1

Michael D. Perloff, Lisa L. von Moltke , Michael H. Court, Tsutomu Kotegawa, Richard I. Shader and David J. Greenblatt

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine (M.D.P., L.L.v.M., M.H.C., T.K., R.I.S., D.J.G.), and the Division of Clinical Pharmacology, New England Medical Center (L.L.v.M., R.I.S., D.J.G.), Boston, Massachusetts.

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 (IC50 range, 0.038-0.049 µM). Ketoconazole also inhibited the formation of both TRZ metabolites and of 4-OH-MDZ formation in mouse liver microsomes (IC50 range, 0.0076-0.025 µM). However, ketoconazole (10 µM) 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.

1 This work supported by Department of Health and Human Service Grants MH34223, MH01237, MH19924, and DA05258.

0022-3565/00/2922-0618$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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