HEPATOBILIARY TRANSPORT KINETICS OF HSR-903, A NEW QUINOLONE ANTIBACTERIAL AGENT

HSR-903 is a newly synthesized quinolone antibacterial agent with low toxicity. The biliary and urinary excretion of unchanged HSR-903, its R-isomer, and their glucuronides was determined after iv bolus adminis tration (5 mg/kg) to normal Sprague-Dawley rats (SDR) and Eisai hyperb ilirubinemic mutant rats (EHBR). The values for the biliary excretion clearance of HSR-903 and its glucuronide in EHBR were decreased to app roximately 40 and 2% of those in SDR, respectively, whereas the values for the urinary excretion clearance of HSR-903 and its glucuronide we re comparable in SDR and EHBR. The biliary excretion clearance values for the R-isomer and its glucuronide were approximately 3 times greate r than those for HSR-903. These results demonstrated that the enantiom ers of HSR-903 and their conjugates were excreted into bile in a stere ospecific manner. The hepatic uptake of [C-14]HSR-903 in vivo was eval uated by means of integration plot analysis. The results indicated tha t the hepatic uptake of [C-14]HSR-903 was very fast and was blood flow -limited. To clarify the mechanism of excretion of HSR-903 into bile, the uptake and efflux of [C-14]HSR-903 were studied using isolated hep atocytes from SDR and EHBR. The initial uptake of HSR-903 by hepatocyt es was temperature-dependent, saturable, and stereospecific. Unlabeled HSR-903 (S-isomer), the R-isomer, grepafloxacin, and sparfloxacin sig nificantly inhibited the uptake of [C-14]HSR-903. The efflux of [14C]H SR-903 from hepatocytes from EHBR was significantly slower than that f rom hepatocytes from SDR. The addition of sodium azide or bromosulfoph thalein reduced the efflux of [C-14]HSR-903. These results demonstrate that HSR-903 is actively excreted into bile via the canalicular multi specific organic anion transporter, which is deficient in EHBR.