Carrier-Mediated Lung Distribution of HSR-903, a New Quinolone Antibacterial Agent1
- 1Department of Pharmacobio-Dynamics, Faculty of Pharmaceutical Sciences, Kanazawa University (M.M., I.T., Y.S., A.T.), Kanazawa, Japan; 2Research and Development Division, Hokuriku Seiyaku Co. (M.M., O.N., H.K.), Inokuchi, Fukui, Japan; and 3Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi, Saitama, Japan (I.T., Y.S., A.T.)
Abstract
HSR-903 [(S)-(−)-5-amino-7-(7-amino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid methanesulfonate] is a newly synthesized quinolone with a potent antibacterial activity and a low toxicity. The lung concentration of unchanged HSR-903 was about nine times higher than that in plasma after oral administration (5 mg/kg) in rats. In comparative studies, HSR-903 was accumulated more efficiently than levofloxacin, ciprofloxacin, and lomefloxacin in rat lung. To clarify the mechanism of the specific distribution of HSR-903 into the lung, the uptake of [14C]HSR-903 was studied using isolated rat lung cells and an isolated rat lung perfusion technique. Initial uptake of HSR-903 by isolated lung cells was temperature dependent, saturable, stereospecific, and Na+ and Cl− dependent. The Hill coefficients (1.90 for Na+ and 1.13 for Cl−) suggest that two Na+ and one Cl− are associated with the transport of one HSR-903 molecule. The uptake of HSR-903 was inhibited by other quinolone antibacterial agents, grepafloxacin, and sparfloxacin. The extraction ratio of HSR-903 in isolated lung perfusion was temperature dependent and saturable. These findings suggest that HSR-903 is taken up by the lung cells via a carrier-mediated transport mechanism, resulting in a concentrative distribution into the lung.
Footnotes
-
Send reprint requests to: Akira Tsuji, Ph.D., Department of Pharmacobio-Dynamics, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan.
-
↵1 This research was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan, the Japan Health Science Foundation, the Drug Innovation Project and the Japan Research Foundation for Clinical Pharmacology.
- Abbreviations:
- Vd
- distribution volume
- KHB
- Krebs-Henseleit buffer
- j
- initial uptake rate
- s, a concentration of the substrate
- Kt, apparent Michaelis constant
- Jmax
- maximal uptake rate
- kd
- nonsaturable uptake clearance
- AUC
- area under the concentration curve
-
- Received December 1, 1997.
- Accepted October 27, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
