Moriwaki Toshiya, Yasui Hiroyuki, Yamamoto Akira
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
Pharm Res. 2004 Jun;21(6):1055-64. doi: 10.1023/b:pham.0000029296.07355.91.
The aim of this study was to characterize the in vivo pharmacokinetics with the enterohepatic circulation (EHC) and identify the role of multidrug resistance-associated protein 2 (MRP2/Mrp2) in biliary excretion and absorption of ramatroban, a thromboxane A2 antagonist using a recirculatory model.
Ramatroban was intravenously or orally administered to Sprague-Dawley rats (SDR) and Eisai hyperbilirubinemic rats (EHBR). Portal and systemic blood and bile samples were collected, and the drug concentrations were analyzed by high-performance liquid chromatography (HPLC) to estimate various global and local moments.
The bioavailability (BA) of ramatroban was estimated at 21.0% in SDR and 61.9% in EHBR. The local absorption ratio for the dosage after oral administration (Fa(dosage)) and the single-pass local absorption ratio for EHC (Fa') in the rats were similar and nearly 100%. The hepatic recovery ratio (Fh) and the single-pass biliary excretion ratio through the liver for the sum of ramatroban and its glucuronides (Fb) in EHBR were 61.4% and 8.88%, respectively, which differed considerably from those in SDR (15.0% and 22.4%). The difference in hepatic elimination between these strains would be caused, at least in part, by the reduced biliary excretion in EHBR, although the biliary excretion was not completely impaired.
Ramatroban may be excreted by multiple transport systems, followed by efficient enterohepatic reabsorption in both strains. The results suggest that ramatroban may not be susceptible to drug-drug interaction involving MRP2/Mrp2 in biliary excretion and absorption.
本研究旨在利用再循环模型表征雷马曲班的肠肝循环（EHC）体内药代动力学，并确定多药耐药相关蛋白2（MRP2/Mrp2）在雷马曲班（一种血栓素A2拮抗剂）胆汁排泄和吸收中的作用。
将雷马曲班静脉注射或口服给予Sprague-Dawley大鼠（SDR）和卫材高胆红素血症大鼠（EHBR）。采集门静脉血、全身血和胆汁样本，通过高效液相色谱（HPLC）分析药物浓度，以估算各种整体和局部矩。
雷马曲班在SDR中的生物利用度（BA）估计为21.0%，在EHBR中为61.9%。大鼠口服给药后剂量的局部吸收比（Fa(dosage)）和EHC的单通道局部吸收比（Fa'）相似，接近100%。EHBR中雷马曲班及其葡糖醛酸化物总和的肝回收率（Fh）和通过肝脏的单通道胆汁排泄率（Fb）分别为61.4%和8.88%，与SDR中的（15.0%和22.4%）有显著差异。尽管胆汁排泄未完全受损，但这些品系之间肝脏消除的差异至少部分是由EHBR中胆汁排泄减少引起的。
雷马曲班可能通过多种转运系统排泄，随后在两种品系中都进行有效的肠肝重吸收。结果表明，雷马曲班在胆汁排泄和吸收中可能不易受到涉及MRP2/Mrp2的药物相互作用的影响。
