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Vol. 26, Issue 11, 1113-1119, November 1998

Hepatobiliary Transport Kinetics of HSR-903, a New Quinolone Antibacterial Agent

Mitsuo Murata, Ikumi Tamai, Yoshimichi Sai, Osamu Nagata, Hideo Kato, Yuichi Sugiyama, and Akira Tsuji

Research and Development Division, Hokuriku Seiyaku Co., Ltd. (M.M., O.N., H.K.), Faculty of Pharmaceutical Sciences, Kanazawa University (M.M., I.T., Y.Sa., A.T.), Faculty of Pharmaceutical Sciences, University of Tokyo (Y.Su.), and CREST, Japan Science and Technology Corporation (A.T.)

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 administration (5 mg/kg) to normal Sprague-Dawley rats (SDR) and Eisai hyperbilirubinemic mutant rats (EHBR). The values for the biliary excretion clearance of HSR-903 and its glucuronide in EHBR were decreased to approximately 40 and 2% of those in SDR, respectively, whereas the values for the urinary excretion clearance of HSR-903 and its glucuronide were comparable in SDR and EHBR. The biliary excretion clearance values for the R-isomer and its glucuronide were approximately 3 times greater than those for HSR-903. These results demonstrated that the enantiomers of HSR-903 and their conjugates were excreted into bile in a stereospecific manner. The hepatic uptake of [14C]HSR-903 in vivo was evaluated by means of integration plot analysis. The results indicated that the hepatic uptake of [14C]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 [14C]HSR-903 were studied using isolated hepatocytes from SDR and EHBR. The initial uptake of HSR-903 by hepatocytes was temperature-dependent, saturable, and stereospecific. Unlabeled HSR-903 (S-isomer), the R-isomer, grepafloxacin, and sparfloxacin significantly inhibited the uptake of [14C]HSR-903. The efflux of [14C]HSR-903 from hepatocytes from EHBR was significantly slower than that from hepatocytes from SDR. The addition of sodium azide or bromosulfophthalein reduced the efflux of [14C]HSR-903. These results demonstrate that HSR-903 is actively excreted into bile via the canalicular multispecific organic anion transporter, which is deficient in EHBR.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 1998 by the American Society for Pharmacology and Experimental Therapeutics.