title: Hepatobiliary transport kinetics of HSR-903, a new quinolone antibacterial agent.
abstract: 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.
authors.affiliation: Research and Development Division, Hokuriku Seiyaku Co., Ltd., Japan.
authors.forename: M
authors.initials: M
authors.lastname: Murata
authors.forename: I
authors.initials: I
authors.lastname: Tamai
authors.forename: Y
authors.initials: Y
authors.lastname: Sai
authors.forename: O
authors.initials: O
authors.lastname: Nagata
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: A
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001659:Biliary Tract / Q000378:metabolism*; D002478:Cells, Cultured; D024841:Fluoroquinolones; D007275:Injections, Intravenous; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; C106426:olamufloxacin