Patki Kiran C, von Moltke Lisa L, Harmatz Jerold S, Hesse Leah M, Court Michael H, Greenblatt David J
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
J Pharmacol Exp Ther. 2004 Mar;308(3):874-9. doi: 10.1124/jpet.103.059311. Epub 2003 Nov 21.
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.
我们使用三唑仑（TRZ）作为CYP3A活性指标，在体外研究了人肝微粒体（HLMs）中与年龄相关的酶动力学参数变化。HLMs取自四个年龄组的男性肝脏，每组n = 5：A组（14 - 20岁）、B组（21 - 40岁）、C组（41 - 60岁）和D组（61 - 72岁）。与A组和D组相比，B组和C组中1 - 羟基三唑仑（1 - OH - TRZ）和4 - 羟基三唑仑（4 - OH - TRZ）形成的平均V(max)值以及净内在清除率（两条途径之和）均显著更高。A、B、C和D组的平均净内在清除率（Cl(int)）值分别为25.2、89.8、78和20.6 nl/min/mg蛋白。TRZ的Cl(int)与总CYP3A含量相关性良好（r(s) = 0.84；P < 0.0001）。睾酮（TST）在所有年龄组中均抑制1 - OH - TRZ的形成并激活4 - OH - TRZ的形成，各组之间无显著差异；这表明以TRZ和TST作为CYP3A底物指标的药物相互作用潜力可能不会随年龄变化。老年男性肝脏中TRZ羟基化和CYP3A蛋白的V(max)和Cl(int)降低表明该组中CYP3A基因表达降低。
