Hebert M F, Fisher R M, Marsh C L, Dressler D, Bekersky I
Department of Pharmacy, University of Washington, Seattle 98195-7630, USA.
J Clin Pharmacol. 1999 Jan;39(1):91-6. doi: 10.1177/00912709922007499.
Tacrolimus is a marketed immunosuppressant used in liver and kidney transplantation. It is subject to extensive metabolism by CYP3A4 and is a substrate for P-glycoprotein-mediated transport. A pharmacokinetic interaction with rifampin, an antituberculosis agent and potent inducer of CYP3A4 and P-glycoprotein, and tacrolimus was evaluated in six healthy male volunteers. Tacrolimus was administered at doses of 0.1 mg/kg orally and 0.025 mg/kg/4 hours intravenously. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected over 96 hours, after single oral and intravenous administration prior to and during an 18-day concomitant rifampin dosing phase. Coadministration of rifampin significantly increased tacrolimus clearance (36.0 +/- 8.1 ml/hr/kg vs. 52.8 +/- 9.6 ml/hr/kg; p = 0.03) and decreased tacrolimus bioavailability (14.4% +/- 5.7% vs. 7.0% +/- 2.7%; p = 0.03). Rifampin appears to induce both intestinal and hepatic metabolism of tacrolimus, most likely through induction of CYP3A and P-glycoprotein in the liver and small bowel.
他克莫司是一种已上市的免疫抑制剂，用于肝脏和肾脏移植。它主要通过CYP3A4进行广泛代谢，并且是P-糖蛋白介导转运的底物。在6名健康男性志愿者中评估了抗结核药物利福平（一种强效的CYP3A4和P-糖蛋白诱导剂）与他克莫司之间的药代动力学相互作用。他克莫司的给药剂量为口服0.1mg/kg，静脉注射0.025mg/kg/4小时。在18天的利福平联合给药阶段之前和期间，单次口服和静脉给药后，从96小时内采集的系列血样中获取他克莫司的药代动力学数据。利福平的联合给药显著增加了他克莫司的清除率（36.0±8.1ml/hr/kg对52.8±9.6ml/hr/kg；p = 0.03）并降低了他克莫司的生物利用度（14.4%±5.7%对7.0%±2.7%；p = 0.03）。利福平似乎诱导了他克莫司在肠道和肝脏的代谢，最有可能是通过诱导肝脏和小肠中的CYP3A和P-糖蛋白。
