van Giersbergen P L M, Treiber A, Schneiter R, Dietrich H, Dingemanse J
Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.
Clin Pharmacol Ther. 2007 Mar;81(3):414-9. doi: 10.1038/sj.clpt.6100075. Epub 2007 Jan 24.
This study was conducted to investigate the effect of rifampin on the pharmacokinetics of bosentan. Healthy male subjects received bosentan 125 mg b.i.d. for 6.5 days in the presence or absence of rifampin 600 mg once a day. In vitro experiments were performed to investigate the effect of rifampin on the uptake of bosentan into Chinese hamster ovary cells expressing the human organic anion-transporting polypeptide (OATP)1B1, -1B3, and -2B1. Following the first concomitant administration, there was a fivefold increase in bosentan trough concentrations. At steady state, concomitant rifampin significantly decreased exposure to bosentan by 58%. Rifampin potently inhibited the uptake of bosentan into cells expressing human OATP1B1 and -1B3. Rifampin decreased the exposure to bosentan consistent with its known cytochrome P450 enzyme-inductive properties. The initial increase in bosentan concentrations can be explained by an inhibitory effect of rifampin on hepatic drug transporters.
本研究旨在探讨利福平对波生坦药代动力学的影响。健康男性受试者在有或无利福平（每日600 mg）的情况下，接受波生坦125 mg每日两次，共6.5天。进行体外实验以研究利福平对波生坦摄取进入表达人有机阴离子转运多肽（OATP）1B1、-1B3和-2B1的中国仓鼠卵巢细胞的影响。首次联合给药后，波生坦谷浓度增加了五倍。在稳态时，联合使用利福平显著降低了波生坦的暴露量，降幅达58%。利福平强烈抑制波生坦摄取进入表达人OATP1B1和-1B3的细胞。利福平降低了波生坦的暴露量，这与其已知的细胞色素P450酶诱导特性相符。波生坦浓度的最初升高可通过利福平对肝药物转运体的抑制作用来解释。
