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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Effect of Age on in Vitro Triazolam Biotransformation in Male Human Liver Microsomes

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

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 V_max 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 (Cl_int) values were 25.2, 89.8, 78, and 20.6 nl/min/mg protein in A, B, C, and D, respectively. TRZ Cl_int correlated well with total CYP3A content (r_s = 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 V_max and Cl_int for TRZ hydroxylation and CYP3A protein in livers from elderly men suggest reduced CYP3A gene expression in this group.

Address correspondence to: Dr. David J. Greenblatt, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. E-mail: dj.greenblatt{at}tufts.edu

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