Abstract
We studied age-related changes in enzyme kinetic parameters in human liver microsomes (HLMs) in vitro, using triazolam (TRZ), an index of CYP3A activity. HLMs were prepared from male livers from four age groups, n = 5 per group: A (14–20 years), B (21–40 years), C (41–60 years), and D (61–72 years). Mean Vmax values in groups B and C for both 1-hydroxytriazolam (1-OH-TRZ) and 4-hydroxy-triazolam (4-OH-TRZ) formation were significantly greater as compared with groups A and D individually, as well as the net intrinsic clearance (sum of the two pathways). The mean net intrinsic clearance (Clint) values were 25.2, 89.8, 78, and 20.6 nl/min/mg protein in A, B, C, and D, respectively. TRZ Clint correlated well with total CYP3A content (rs = 0.84; P < 0.0001). Testosterone (TST) inhibited 1-OH-TRZ formation and activated 4-OH-TRZ formation in all age groups, with no significant differences among the groups; this suggests that the drug-drug interaction potential using TRZ and TST as index CYP3A substrates may not change with age. Reduced Vmax and Clint for TRZ hydroxylation and CYP3A protein in livers from elderly men suggest reduced CYP3A gene expression in this group.
Footnotes
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Supported by Grants MH-58435, DA-13209, DA-13834, DK-58496, DA-05258, GM-61834, AG-17880, MH-01237, and RR-00054 from the Department of Health and Human Services. Dr. Patki is supported by the Tufts-Pfizer Fellowship Program in Clinical Pharmacology.
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Presented in part at the 2003 annual meeting of the American Society of Clinical Pharmacology and Therapeutics in Washington, D.C., April 2–5, 2003.
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DOI: 10.1124/jpet.103.059311.
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ABBREVIATIONS: TRZ, triazolam; 1-OH-TRZ, 1-hydroxy-triazolam; 4-OH-TRZ, 4-hydroxy-triazolam; HLM, human liver microsome; P450, cytochrome P-450; TST, testosterone; DDI, drug-drug interaction; HPLC, high-performance liquid chromatography; HRP, horseradish peroxidase; ANOVA, analysis of variance.
- Received August 29, 2003.
- Accepted November 13, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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