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Vol. 292, Issue 3, 1024-1031, March 2000

Effects of Age on In Vitro Midazolam Biotransformation in Male CD-1 Mouse Liver Microsomes1

Jill S. Warrington, Joseph W. Poku, Lisa L. von Moltke, Richard I. Shader, Jerold S. Harmatz and David J. Greenblatt

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and the Division of Clinical Pharmacology, New England Medical Center, Boston, Massachusetts

To study age-related changes in drug metabolism, we examined the in vitro biotransformation of midazolam (MDZ), a human cytochrome P-450 (CYP) 3A substrate, using liver microsomes from three age groups of male CD-1 mice ranging from 6 weeks to 2 years old. MDZ was metabolized to two major products, alpha -OH- and 4-OH-MDZ, which were quantified by HPLC. For both metabolites, Vmax values were reduced in old livers (P < .05), while Km values did not change with age. The net intrinsic clearance (the sum of Vmax/Km for both pathways) also was reduced in the old animals (P < .05). The capacity of ketoconazole, a CYP3A inhibitor in humans, to inhibit the biotransformation of MDZ and of alprazolam, another human CYP3A substrate, did not differ significantly with age. At 100 µM alprazolam, 0.5µM ketoconazole inhibited metabolite formation by >80%. At 30 µM MDZ, 2.5 µM ketoconazole impaired 4-OH-MDZ formation by 88%, whereas it reduced alpha -OH-MDZ formation by only 46%. Immunoinhibition studies with polyclonal anti-rat CYP3A1/2 and CYP2C11 antibodies confirmed that 4-OH-MDZ formation was largely CYP3A-dependent, while alpha -OH-MDZ formation was mediated by CYP3A and -2C isoforms. Western blot analysis revealed decreased microsomal content of CYP3A in old livers. Net intrinsic clearance of MDZ was correlated with total CYP3A content (P < .001). These results demonstrate a reduction in MDZ biotransformation in old male mice, which may be attributable, in part, to decreased CYP3A content in old livers. Changes in expression and activity of CYP2C isoforms also may contribute to age-related changes in MDZ biotransformation, but this requires more investigation.

1 This work was funded, in part, by a grant from the John A. Hartford/AFAR Medical Students Geriatric Scholars Program and by Grants MH-34223, DA-05258, MH-19924, and RR-00054 from the Department of Health and Human Services. Dr. von Moltke is the recipient of a Scientist Development Award (K21-MH-01237) from the National Institutes of Mental Health.

0022-3565/00/2923-1024$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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