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.
Footnotes
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Send reprint requests to: Akira Tsuji, Ph.D., Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan.
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This research was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan.
- Abbreviations used are::
- EHBR
- Eisai hyperbilirubinemic mutant rat(s)
- SDR
- Sprague-Dawley rat(s)
- BSP
- bromosulfophthalein
- CLbile
- biliary excretion clearance
- CLurine
- urinary excretion clearance
- cMOAT
- canalicular multispecific organic anion transporter
- Cp,t
- plasma concentration at time t
- Cliver
- t, drug amount per gram of wet tissue at time t
- CLuptake
- hepatic uptake clearance
- Kt
- apparent Michaelis constant
- Jmax
- maximal uptake rate
- kd
- nonsaturable uptake clearance
- PSu,influx
- membrane permeability clearance
- CLint,liver
- intrinsic hepatic uptake clearance
- CLtot
- total body clearance
- Received December 1, 1997.
- Accepted May 8, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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