Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
J Pharm Pharm Sci. 2012;15(2):318-28. doi: 10.18433/j3ms40.
A few studies have shown that normothermic hepatic ischemia-reperfusion (IR) injury may affect the mRNA and/or protein levels of canalicular transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2). However, the effects of the injury on the functions of these canalicular transporters with respect to the biliary excretion of drugs remain largely unknown. Therefore, the purpose of this study was to investigate the effects of warm hepatic IR on the hepatobiliary disposition of rhodamine 123 (RH-123), a P-gp substrate, and its glucuronidated metabolite (RH-Glu), an Mrp2 substrate, in rats.
Twenty four or 72 h following a 60-min partial ischemia or sham operation in rats, livers were isolated and perfused ex vivo with a constant concentration (~100 ng/mL) of RH-123. The concentration of RH-123 and its glucuronidated (RH-Glu) and deacylated (RH-110) metabolites were determined in the outlet perfusate, bile, and the liver tissue using HPLC, and relevant pharmacokinetic parameters were estimated.
Twenty-four-h IR caused a significant reduction in the hepatic extraction ratio of RH-123 (IR: 0.857 ± 0.078; Sham: 0.980 ± 0.017) and the biliary recovery of the parent drug and RH-Glu by 43% and 44%, respectively. The reductions in the biliary recovery were associated with significant reductions in the apparent biliary clearance of RH-123 and RH-Glu. Mass balance data showed that the formation of the glucuronidated or deacylated metabolite was not significantly affected by the 24-h IR injury. In contrast to the 24-h IR, the injury did not have any effect on the hepatobiliary disposition of RH-123 or its metabolites following 72 h of reperfusion.
It is concluded that the pharmacokinetics of drugs that are subject to biliary excretion by the canalicular P-gp and Mrp2 transporters may be altered shortly after hepatic IR injury.
有几项研究表明，常温肝缺血再灌注（IR）损伤可能会影响胆小管转运蛋白 P 糖蛋白（P-gp）和多药耐药相关蛋白 2（Mrp2）的 mRNA 和/或蛋白水平。然而，这种损伤对这些胆小管转运体的功能，以及药物的胆汁排泄的影响在很大程度上仍是未知的。因此，本研究的目的是研究温肝 IR 对 rhodamine 123（RH-123），一种 P-gp 底物，及其葡萄糖醛酸化代谢物（RH-Glu），一种 Mrp2 底物在大鼠中的肝胆处置的影响。
在大鼠进行 60 分钟部分缺血或假手术后 24 或 72 小时，将肝脏分离并进行离体灌注，灌注液中含有恒定浓度（~100ng/mL）的 RH-123。使用 HPLC 测定出口灌流液、胆汁和肝组织中 RH-123 及其葡萄糖醛酸化（RH-Glu）和脱酰化（RH-110）代谢物的浓度，并估算相关药代动力学参数。
24 小时 IR 导致 RH-123 的肝摄取率（IR：0.857±0.078；Sham：0.980±0.017）和母体药物及 RH-Glu 的胆汁回收率分别显著降低 43%和 44%。胆汁回收的减少与 RH-123 和 RH-Glu 的表观胆汁清除率显著降低有关。质量平衡数据表明，24 小时 IR 损伤对葡萄糖醛酸化或脱酰化代谢物的形成没有显著影响。与 24 小时 IR 不同，72 小时再灌注后，IR 损伤对 RH-123 及其代谢物的肝胆处置没有任何影响。
综上所述，在肝 IR 损伤后不久，经胆小管 P-gp 和 Mrp2 转运体胆汁排泄的药物的药代动力学可能会发生改变。
