Vol. 284, Issue 2, 661-668, February 1998

Stereoselective Hepatobiliary Transport of the Quinolone Antibiotic Grepafloxacin and Its Glucuronide in the Rat

Hiroyuki Sasabe, Yukio Kato, Akira Tsuji and Yuichi Sugiyama

Faculty of Pharmaceutical Sciences (H.S., Y.K., Y.S.), University of Tokyo, Tokyo, Japan and Faculty of Pharmaceutical Sciences (A.T.), University of Kanazawa, Ishikawa, Japan

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 the V_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 a K_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 ratspossibly by the bile canalicular multispecific organic anion transport system.