PT  - JOURNAL ARTICLE
AU  - Mitsuo Murata
AU  - Ikumi Tamai
AU  - Yoshimichi Sai
AU  - Osamu Nagata
AU  - Hideo Kato
AU  - Yuichi Sugiyama
AU  - Akira Tsuji
TI  - Hepatobiliary Transport Kinetics of HSR-903, a New Quinolone Antibacterial Agent
DP  - 1998 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1113--1119
VI  - 26
IP  - 11
4099  - http://dmd.aspetjournals.org/content/26/11/1113.short
4100  - http://dmd.aspetjournals.org/content/26/11/1113.full
SO  - Drug Metab Dispos1998 Nov 01; 26
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics