Vol. 289, Issue 1, 79-84, April 1999

Carrier-Mediated Lung Distribution of HSR-903, a New Quinolone Antibacterial Agent¹

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

Department of Pharmacobio-Dynamics, Faculty of Pharmaceutical Sciences, Kanazawa University (M.M., I.T., Y.S., A.T.), Kanazawa, Japan; Research and Development Division, Hokuriku Seiyaku Co. (M.M., O.N., H.K.), Inokuchi, Fukui, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi, Saitama, Japan (I.T., Y.S., A.T.)

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.