Okura Takashi, Morita Yuki, Ito Yoshihiko, Kagawa Yoshiyuki, Yamada Shizuo
Department of Pharmacokinetics, Pharmacodynamics, Global Center of Excellence (COE) and Clinical Pharmaceutics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
J Pharm Pharmacol. 2009 May;61(5):593-7. doi: 10.1211/jpp/61.05.0007.
The aim of this study was to investigate the effect of quinidine, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of morphine in rats.
Rats were given morphine (30 mg/kg p.o. or 30 mg/kg over 10 min i.v.) 30 min after pretreatment with quinidine (30 mg/kg p.o.). Antinociceptive effects were determined using the tail immersion test. Concentrations of morphine in plasma and brain were also determined.
The antinociception of morphine was significantly enhanced by oral administration of quinidine, with a 3.1-fold greater area under the effect-time curve than that in vehicle-treated rats. Morphine concentrations in plasma and brain were significantly increased by quinidine. The area under the plasma concentration-time curve after oral or intravenous administration of morphine was increased 5.2- and 1.7-fold, respectively, in quinidine-pretreated rats compared with vehicle-pretreated rats. Quinidine caused a 40% decrease in the total clearance of morphine and increased the concentration of morphine in the brain, although the brain-to-plasma concentration ratio was not changed.
Oral administration of quinidine increases the absorption of morphine from the gastrointestinal tract and subsequently enhances the concentration in the brain and its antinociceptive effect. Enhanced intestinal absorption of morphine may be due largely to inhibition of intestinal P-glycoprotein by quinidine.
本研究旨在探讨P-糖蛋白抑制剂奎尼丁对大鼠体内吗啡药代动力学和药效学的影响。
大鼠在经口给予奎尼丁（30mg/kg）预处理30分钟后，给予吗啡（30mg/kg经口或30mg/kg在10分钟内静脉注射）。使用尾浸试验测定镇痛效果。同时测定血浆和脑中吗啡的浓度。
口服奎尼丁可显著增强吗啡的镇痛作用，其效应-时间曲线下面积比给予赋形剂的大鼠大3.1倍。奎尼丁可使血浆和脑中吗啡浓度显著升高。与给予赋形剂预处理的大鼠相比，奎尼丁预处理的大鼠经口或静脉注射吗啡后血浆浓度-时间曲线下面积分别增加了5.2倍和1.7倍。奎尼丁使吗啡的总清除率降低40%，并增加了脑中吗啡的浓度，尽管脑-血浆浓度比未改变。
口服奎尼丁可增加吗啡从胃肠道的吸收，进而提高脑中浓度及其镇痛效果。吗啡肠道吸收增强可能主要归因于奎尼丁对肠道P-糖蛋白的抑制作用。
