Abstract

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/K_m) of S-GPFX-Glu for the transporter was 1.7 times higher than that of R-GPFX-Glu, whereas theV_max 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 aK_i of 21.5 μM and 8.8 μM for R-GPFX-Glu and S-GPFX-Glu, respectively. These K_i values were comparable with the corresponding Michaelis-Menten constant values for their uptake (17.3 μM and 10.1 μM, 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.