Yan Dongmei, Yang Yingbao, Uchida Sinya, Misaka Shingen, Luo Jinghui, Takeuchi Kazuhiko, Inui Naoki, Yamada Shizuo, Ohashi Kyoichi, Watanabe Hiroshi
Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, 431-3129, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2008 Jun;377(4-6):629-36. doi: 10.1007/s00210-007-0217-z. Epub 2007 Dec 19.
Animal and in vitro studies suggest that ursodeoxycholic acid (UDCA) can induce cytochrome P450 3A (CYP3A) expression and enhance its activities. On the other hand, Becquemont et al. demonstrated that UDCA had no influence on intestinal CYP3A activities. The aim of this study was to investigate the effects of UDCA on the intestinal and hepatic CYP3A activities by administration of midazolam (MDZ), as a specific probe for CYP3A activity, in humans. This was a randomized, open-label, crossover study with two phases in 14 healthy volunteers. The volunteers received UDCA (300 mg/day) or placebo orally for 9 days. The pharmacokinetics and pharmacodynamics of intravenous MDZ (5 microg/kg) and oral MDZ (15 microg/kg) were assessed on days 8 and 9, respectively. The pharmacodynamics of MDZ was estimated by measuring peak saccadic velocity, postural away length, critical fusion flicker frequency, and visual analogue scale. UDCA did not affect the pharmacokinetic and pharmacodynamic parameters of intravenous and oral MDZ administrations. Our study suggests that the clinical dosage of UDCA could not affect both hepatic and intestinal CYP3A activities and that the drug interaction between UDCA and substrates for CYP3A is unlikely in humans.
动物和体外研究表明，熊去氧胆酸（UDCA）可诱导细胞色素P450 3A（CYP3A）表达并增强其活性。另一方面，Becquemont等人证明UDCA对肠道CYP3A活性没有影响。本研究的目的是通过给予咪达唑仑（MDZ）作为CYP3A活性的特异性探针，来研究UDCA对人体肠道和肝脏CYP3A活性的影响。这是一项针对14名健康志愿者的两阶段随机、开放标签、交叉研究。志愿者口服UDCA（300毫克/天）或安慰剂，为期9天。分别在第8天和第9天评估静脉注射MDZ（5微克/千克）和口服MDZ（15微克/千克）的药代动力学和药效学。通过测量峰值扫视速度、姿势偏离长度、临界融合闪烁频率和视觉模拟量表来评估MDZ的药效学。UDCA不影响静脉注射和口服MDZ给药的药代动力学和药效学参数。我们的研究表明，UDCA的临床剂量不会影响肝脏和肠道的CYP3A活性，并且在人类中UDCA与CYP3A底物之间的药物相互作用不太可能发生。
