老年人中咪达唑仑与克拉霉素的相互作用。
Interaction between midazolam and clarithromycin in the elderly.
作者信息
Quinney Sara K, Haehner Barbara D, Rhoades Melissa B, Lin Zhen, Gorski J Christopher, Hall Stephen D
机构信息
Division of Clinical Pharmacology, Indiana University School of Medicine, Wishard Memorial Hospital, W7123 Myers Building, Indianapolis, IN 46202-2879, USA.
出版信息
Br J Clin Pharmacol. 2008 Jan;65(1):98-109. doi: 10.1111/j.1365-2125.2007.02970.x. Epub 2007 Jul 17.
AIM
To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrate midazolam and clarithromycin in the elderly.
METHODS
On day 1, 16 volunteers (eight male, eight female) aged 65-75 years weighing 59-112 kg received simultaneous doses of midazolam intravenously (i.v.) (0.05 mg kg(-1) over 30 min) and orally (p.o.) (3.5 mg of a stable isotope, (15)N(3)-midazolam). Starting on day 2, clarithromycin 500 mg was administered orally twice daily for 7 days. On day eight, i.v. and p.o. doses of midazolam were administered 2 h after the final clarithromycin dose. Serum and urine samples were assayed for midazolam, (15)N(3)-midazolam and metabolites by gas chromatography/mass spectometry.
RESULTS
Men and women exhibited similar i.v. (30.4 vs. 36.0 l h(-1)) and p.o. (119 vs. 124 l h(-1)) clearances of midazolam. Midazolam hepatic availability was significantly (P = 0.006) greater in men [0.79, 95% confidence interval (CI) 0.75, 0.84] than in women (0.66, 95% CI 0.59, 0.73), but midazolam intestinal availability (0.39 vs. 0.55) was not different. Following clarithromycin dosing, a significant decrease in systemic (33.2 l h(-1) to 11.5 l h(-1)) and oral (121 l h(-1) to 17.4 l h(-1)) midazolam clearance occurred. Oral, hepatic and intestinal availability was significantly increased after clarithromycin dosing from 0.34 to 0.72, 0.73 to 0.91 and 0.47 to 0.79, respectively. Clarithromycin administration led to an increase in the AUC of midazolam by 3.2-fold following i.v. dosing and 8.0-fold following p.o. dosing. Similar effects were observed for males and females.
CONCLUSIONS
Intestinal and hepatic CYP3A inhibition by clarithromycin significantly reduces the clearance of midazolam in the elderly.
目的
评估肠道和肝脏中细胞色素P450 3A（CYP3A）抑制作用对老年人群中CYP3A原型底物咪达唑仑与克拉霉素相互作用的相对贡献。
方法
第1天，16名年龄在65 - 75岁、体重59 - 112 kg的志愿者（8名男性，8名女性）同时静脉注射（i.v.）咪达唑仑（0.05 mg·kg⁻¹，30分钟内注射完毕）和口服（p.o.）咪达唑仑（3.5 mg稳定同位素标记的¹⁵N₃ - 咪达唑仑）。从第2天开始，每天口服克拉霉素500 mg，共7天。第8天，在最后一次克拉霉素给药2小时后，再次静脉注射和口服咪达唑仑。采用气相色谱/质谱法测定血清和尿液样本中的咪达唑仑、¹⁵N₃ - 咪达唑仑及其代谢产物。
结果
男性和女性咪达唑仑的静脉清除率（分别为30.4和36.0 l·h⁻¹）和口服清除率（分别为119和124 l·h⁻¹）相似。男性咪达唑仑的肝脏可用性（0.79，95%置信区间[CI] 0.75，0.84）显著高于女性（0.66，95% CI 0.59，0.73）（P = 0.006），但咪达唑仑的肠道可用性（分别为0.39和0.55）无差异。服用克拉霉素后，咪达唑仑的全身清除率（从33.2 l·h⁻¹降至11.5 l·h⁻¹）和口服清除率（从121 l·h⁻¹降至17.4 l·h⁻¹）显著降低。服用克拉霉素后，口服、肝脏和肠道可用性分别从0.34显著增加至0.72、从0.73增加至0.91、从0.47增加至0.79。静脉注射咪达唑仑后，克拉霉素使咪达唑仑的曲线下面积（AUC）增加3.2倍，口服给药后增加8.0倍。男性和女性观察到相似的效果。
结论
克拉霉素对肠道和肝脏CYP3A的抑制作用显著降低了老年人群中咪达唑仑的清除率。
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