Hughes C M, Swanton J G, Collier P S
School of Pharmacy, Queen's University of Belfast, UK.
J Pharm Pharmacol. 1994 Dec;46(12):1029-31. doi: 10.1111/j.2042-7158.1994.tb03261.x.
The rat in-situ perfused liver model was used to investigate the effect of three H2-receptor antagonists on the pharmacokinetic disposition of the short-acting benzodiazepine, midazolam. Perfusion experiments, using standard techniques, were carried out on four groups (one control and three H2-receptor antagonist-treated groups) of male Sprague-Dawley rats (300-350 g). All animals received midazolam 1 mg; the three treated groups received cimetidine (8 mg), ranitidine (3 mg) or famotidine (0.4 mg). Perfusate and bile samples were collected and assayed for midazolam using gas chromatography. The perfusate data indicated that midazolam disposition was impaired at 10, 50 and 60 min of the experimental period following the addition of cimetidine, whereas ranitidine and famotidine produced an effect at 10 min only; midazolam levels in bile were not affected by the presence of an H2-receptor antagonist. It was concluded that the limited inhibitory effect of cimetidine may be attributed to its lack of specificity for CYP3A, the isoenzyme responsible for the metabolism of midazolam.
采用大鼠原位灌注肝模型研究三种H2受体拮抗剂对短效苯二氮䓬类药物咪达唑仑药代动力学处置的影响。使用标准技术对四组雄性Sprague-Dawley大鼠（300 - 350 g）（一组为对照组，三组为H2受体拮抗剂治疗组）进行灌注实验。所有动物均给予1 mg咪达唑仑；三个治疗组分别给予西咪替丁（8 mg）、雷尼替丁（3 mg）或法莫替丁（0.4 mg）。收集灌注液和胆汁样本，采用气相色谱法测定咪达唑仑含量。灌注液数据表明，加入西咪替丁后，在实验期的10、50和60分钟时咪达唑仑的处置受到损害，而雷尼替丁和法莫替丁仅在10分钟时产生影响；胆汁中咪达唑仑水平不受H2受体拮抗剂的影响。得出的结论是，西咪替丁有限的抑制作用可能归因于其对负责咪达唑仑代谢的同工酶CYP3A缺乏特异性。
