Carrier-mediated lung distribution of HSR-903, a new quinolone antibacterial agent

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 methanesulf onate] is a newly synthesized quinolone with a potent antibacterial activit y 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 t han levofloxacin, ciprofloxacin, and lomefloxacin in rat lung. To clarify t he mechanism of the specific distribution of HSR-903 into the lung, the upt ake of [C-14]HSR-903 was studied using isolated rat lung cells and an isola ted rat lung perfusion technique. Initial uptake of HSR-903 by isolated lun g cells was temperature dependent, saturable, stereospecific, and Na+ and C l- 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 antibacter ial agents, grepafloxacin, and sparfloxacin. The extraction ratio of HSR-90 3 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 int o the lung.