Sasabe H, Kato Y, Tsuji A, Sugiyama Y
Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
J Pharmacol Exp Ther. 1998 Feb;284(2):661-8.
A comparative pharmacokinetic study was performed for the optical isomers of grepafloxacin (GPFX), an asymmetric quinolone antibiotic. At steady state in rats receiving a constant infusion of each epimer, R(+)-GPFX and S(-)-GPFX, no marked difference between epimers was observed in plasma concentrations or in biliary and urinary excretion rates. The 3-glucuronides of GPFX are diastereomers. The biliary clearance, defined by the liver concentration of the 3-glucuronide of R(+)-GPFX (R-GPFX-Glu), was twice that of the 3-glucuronide of S(-)-GPFX (S-GPFX-Glu). Marked ATP dependence was observed in the uptake of both R-GPFX-Glu and S-GPFX-Glu by bile canalicular membrane vesicles. The ATP-dependent uptake of R-GPFX-Glu was also greater than that of S-GPFX-Glu. Kinetic analysis of the uptake of these glucuronides by bile canalicular membrane vesicles indicated that the affinity (1/Km) of S-GPFX-Glu for the transporter was 1.7 times higher than that of R-GPFX-Glu, whereas the Vmax of R-GPFX-Glu was 2.9 times greater than that of S-GPFX-Glu. The uptake of both glucuronides was reduced in mutant strain Eisai-hyperbilirubinemia rats, which have a hereditary defect in the bile canalicular multispecific organic anion transport system. Both glucuronides inhibited the ATP-dependent uptake of DNP-SG, a typical substrate for the bile canalicular multispecific organic anion transport system in a concentration-dependent manner, with a Ki of 21.5 microM and 8.8 microM for R-GPFX-Glu and S-GPFX-Glu, respectively. These Ki values were comparable with the corresponding Michaelis-Menten constant values for their uptake (17.3 microM and 10.1 microM, respectively). It is concluded that a major part of the stereoselective transport of these glucuronides across the bile canalicular membrane is mediated by a transporter that is deficient in Eisai-hyperbilirubinemia rats-possibly by the bile canalicular multispecific organic anion transport system.
对不对称喹诺酮类抗生素格帕沙星（GPFX）的光学异构体进行了比较药代动力学研究。在持续输注每种差向异构体R(+)-GPFX和S(-)-GPFX的大鼠体内达到稳态时，在血浆浓度、胆汁和尿液排泄率方面未观察到差向异构体之间有明显差异。GPFX的3-葡萄糖醛酸苷是非对映异构体。由R(+)-GPFX的3-葡萄糖醛酸苷（R-GPFX-Glu）的肝脏浓度定义的胆汁清除率是S(-)-GPFX的3-葡萄糖醛酸苷（S-GPFX-Glu）的两倍。在胆小管膜囊泡摄取R-GPFX-Glu和S-GPFX-Glu的过程中均观察到明显的ATP依赖性。R-GPFX-Glu的ATP依赖性摄取也大于S-GPFX-Glu。对这些葡萄糖醛酸苷被胆小管膜囊泡摄取的动力学分析表明，S-GPFX-Glu对转运体的亲和力（1/Km）比R-GPFX-Glu高1.7倍，而R-GPFX-Glu的Vmax比S-GPFX-Glu大2.9倍。在Eisai高胆红素血症突变大鼠中，这两种葡萄糖醛酸苷的摄取均减少，该大鼠在胆小管多特异性有机阴离子转运系统中存在遗传性缺陷。两种葡萄糖醛酸苷均以浓度依赖性方式抑制DNP-SG（胆小管多特异性有机阴离子转运系统的典型底物）的ATP依赖性摄取，R-GPFX-Glu和S-GPFX-Glu的Ki分别为21.5 microM和8.8 microM。这些Ki值与其摄取的相应米氏常数（分别为17.3 microM和10.1 microM）相当。得出的结论是，这些葡萄糖醛酸苷跨胆小管膜的立体选择性转运的主要部分是由Eisai高胆红素血症大鼠中缺乏的一种转运体介导的——可能是由胆小管多特异性有机阴离子转运系统介导的。
