唑吡坦在老年人和年轻人中的药代动力学特性：男性体内睾酮可能的调节作用。
Pharmacokinetic properties of zolpidem in elderly and young adults: possible modulation by testosterone in men.
作者信息
Olubodun Joel O, Ochs Hermann R, von Moltke Lisa L, Roubenoff Ronenn, Hesse Leah M, Harmatz Jerold S, Shader Richard I, Greenblatt David J
机构信息
Department of Pharmacology and Experimental Therapeutics and the Jean Mayer USDA Human Nutrition Research Center on Ageing, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
出版信息
Br J Clin Pharmacol. 2003 Sep;56(3):297-304. doi: 10.1046/j.0306-5251.2003.01852.x.
AIMS
The influence of ageing on the pharmacokinetics of zolpidem, an extensively prescribed hypnotic medication, was evaluated in healthy human volunteers.
METHODS
A series of 16 elderly (age: 61-85 years) and 24 young (age: 22-42 years) volunteers received single 5 mg oral doses of zolpidem tartrate. Serum zolpidem concentrations were determined by HPLC with fluorescence detection in samples drawn during 8 h after dosage. The effect of testosterone on zolpidem biotransformation was evaluated in vitro using human liver microsomes. Possible induction of CYP3A protein expression and function was studied in cultured human hepatocytes.
RESULTS
Among men, apparent oral clearance of zolpidem was decreased in elderly compared to young subjects (3.8 vs 11.0 ml min-1 kg-1, P < 0.01), Cmax was increased (93 vs 40 ng ml-1, P < 0.01), and half-life increased (2.7 vs 1.5 h, P < 0.03). Among women, zolpidem oral clearance was decreased in the elderly (3.0 vs 5.8 ml min-1 kg-1, P < 0.02), Cmax increased (108 vs 60 ng ml-1, P < 0.001), with no difference in t1/2 (2.3 vs 2.4 h). Among male subjects, free serum testosterone concentrations were lower in the elderly (10.5 vs 19.0 pg ml-1, P < 0.01), and were significantly correlated with zolpidem clearance (r2 = 0.46, P < 0.001). Multiple regression analysis indicated a greater relative contribution of serum testosterone than age to the oral clearance of zolpidem among men. In human liver microsomes, co-incubation of zolpidem (10 micro m) with varying concentrations of testosterone produced activation of biotransformation of zolpidem to its principal hydroxylated metabolite. Maximum activation was achieved at equimolar concentrations of testosterone (10 micro m). However, testosterone did not induce immunoactive CYP3A4 expression or catalytic function in cultured human hepatocytes.
CONCLUSIONS
The increased Cmax and lower oral clearance of zolpidem in the elderly are consistent with recommendations of lower clinical doses of zolpidem in the elderly. Our clinical and in vitro data both suggest that reduced free serum testosterone may have a modulatory role in age-dependent changes in zolpidem pharmacokinetics in men.
目的
在健康人类志愿者中评估衰老对广泛使用的催眠药物唑吡坦药代动力学的影响。
方法
16名老年志愿者（年龄61 - 85岁）和24名年轻志愿者（年龄22 - 42岁）接受单次5毫克口服酒石酸唑吡坦剂量。给药后8小时内采集的样本通过高效液相色谱荧光检测法测定血清唑吡坦浓度。使用人肝微粒体在体外评估睾酮对唑吡坦生物转化的影响。在培养的人肝细胞中研究CYP3A蛋白表达和功能的可能诱导情况。
结果
在男性中，与年轻受试者相比，老年受试者唑吡坦的表观口服清除率降低（3.8对11.0毫升·分钟⁻¹·千克⁻¹，P < 0.01），Cmax升高（93对40纳克·毫升⁻¹，P < 0.01），半衰期延长（2.7对1.5小时，P < 0.03）。在女性中，老年受试者唑吡坦口服清除率降低（3.0对5.8毫升·分钟⁻¹·千克⁻¹，P < 0.02），Cmax升高（108对60纳克·毫升⁻¹，P < 0.001），t1/2无差异（2.3对2.4小时）。在男性受试者中，老年受试者游离血清睾酮浓度较低（10.5对19.0皮克·毫升⁻¹' P < O.01），且与唑吡坦清除率显著相关（r² = 0.46，P < 0.001）。多元回归分析表明，在男性中，血清睾酮对唑吡坦口服清除率的相对贡献大于年龄。在人肝微粒体中，将唑吡坦（10微摩尔）与不同浓度的睾酮共同孵育可使唑吡坦生物转化为其主要羟基化代谢产物的过程激活。在睾酮等摩尔浓度（10微摩尔）时达到最大激活。然而，睾酮在培养的人肝细胞中未诱导免疫活性CYP3A4表达或催化功能。
结论
老年人中唑吡坦Cmax升高和口服清除率降低与老年人临床使用较低剂量唑吡坦的建议一致。我们的临床和体外数据均表明，游离血清睾酮降低可能在男性唑吡坦药代动力学的年龄依赖性变化中起调节作用。
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