Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
Biopharm Drug Dispos. 2009 Sep;30(6):326-33. doi: 10.1002/bdd.671.
The purpose of this study was to evaluate the mechanisms responsible for the pharmacokinetic variability of bosentan utilizing rats with liver dysfunction induced by 7-day bile duct ligation (BDL). Bosentan was administered intravenously at a constant infusion rate (I) of 24, 40 or 60 microg/min/kg. The blood bosentan concentration (BBC) following infusion was measured by HPLC, and apparent clearance (CL) of the drug was estimated as I/BBC. The CL values in normal rats were 30.5 and 19.3 ml/min/kg at infusion rates of 24 and 60 microg/min/kg, respectively, suggesting non-linear pharmacokinetics of bosentan. The BBC in BDL rats was much higher than that in normal rats, and the CL values in BDL rats were 3.80 and 3.08 ml/min/kg at infusion rates of 24 and 60 microg/min/kg, respectively. The CL value of bosentan at an infusion rate of 40 microg/min/kg in normal rats was decreased significantly by the coadministration of taurocholic acid or bilirubin. In addition, the hepatic mRNA expression of CYP2C6, CYP3A2, Oatp1a1, Oatp1a4 and Oatp1b2 in BDL rats decreased to 77.6%, 34.0%, 65.4%, 84.8% and 44.2% of that in normal rats, respectively. These results suggested that bile acids and/or bilirubin accumulated in BDL rat plasma inhibited the hepatic uptake of bosentan, and that the decreased bosentan clearance in BDL rats was caused at least partly by the impaired expression of hepatic drug-metabolizing enzymes and uptake transporters. Moreover, because the pharmacokinetics of bosentan was non-linear at the tested doses, the increased BBC in BDL rats might further induce the saturation of hepatic uptake and/or metabolism of bosentan.
本研究旨在评估胆汁淤积性肝损伤大鼠中导致波生坦药代动力学变异性的机制。波生坦以 24、40 或 60μg/min/kg 的恒定输注速率（I）静脉输注。输注后通过 HPLC 测定血中波生坦浓度（BBC），并将药物的表观清除率（CL）估计为 I/BBC。正常大鼠在输注速率为 24 和 60μg/min/kg 时的 CL 值分别为 30.5 和 19.3ml/min/kg，表明波生坦的药代动力学呈非线性。BDL 大鼠的 BBC 明显高于正常大鼠，BDL 大鼠在输注速率为 24 和 60μg/min/kg 时的 CL 值分别为 3.80 和 3.08ml/min/kg。正常大鼠输注速率为 40μg/min/kg 时，牛磺胆酸或胆红素共给药可显著降低波生坦的 CL 值。此外，BDL 大鼠肝 CYP2C6、CYP3A2、Oatp1a1、Oatp1a4 和 Oatp1b2 的 mRNA 表达分别下降至正常大鼠的 77.6%、34.0%、65.4%、84.8%和 44.2%。这些结果表明，BDL 大鼠血浆中胆汁酸和/或胆红素的蓄积抑制了波生坦的肝摄取，而 BDL 大鼠中波生坦清除率的降低至少部分是由肝药物代谢酶和摄取转运体表达减少引起的。此外，由于波生坦的药代动力学在测试剂量下是非线性的，BDL 大鼠中增加的 BBC 可能进一步诱导波生坦的肝摄取和/或代谢饱和。
