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0090-9556/03/3111-1409-1418$20.00
DMD 31:1409-1418, 2003

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METABOLISM AND DISPOSITION OF NOVEL DES-FLUORO QUINOLONE GARENOXACIN IN EXPERIMENTAL ANIMALS AND AN INTERSPECIES SCALING OF PHARMACOKINETIC PARAMETERS

Hiroyoshi Hayakawa, Yoko Fukushima, Hiroshi Kato, Hiroyuki Fukumoto, Takumi Kadota, Hiroyuki Yamamoto, Hiroyuki Kuroiwa, Junko Nishigaki, and Akira Tsuji

Department of Drug Safety Research Laboratory, Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan (H.H., Y.F., H.K., H.F, T.K., H.Y.); Institute of Whole Body Metabolism, Chiba, Japan (H.K., J.N.); and Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (A.T.)

Garenoxacin is a novel quinolone that does not have a fluorine substituent at the C-6 position in the quinoline ring. Garenoxacin or14C-garenoxacin was intravenously or orally administered to rats, dogs, and monkeys. Metabolic profiles and pharmacokinetic parameters were investigated focusing on the species differences and the allometric scaling of pharmacokinetic parameters. Garenoxacin was well absorbed following oral administration then underwent phase II metabolism in all species tested. Major metabolites of garenoxacin were the sulfate of garenoxacin (M1) and glucuronide (M6). Oxidative metabolites were present in very minor concentrations in all species tested. Another minor route of metabolism was the formation of the carbamoyl glucuronide. Garenoxacin is characterized across species by the observation that it circulates systemically, is excreted renally as unchanged drug, and is metabolized to M1 and M6, which are excreted specifically into the bile. The total clearances (CL) were 12.1, 2.43, and 3.39 ml/min/kg for rats, dogs, and monkeys, respectively. The distribution volume values of garenoxacin (Vss) were 0.88, 1.29, and 0.96 l/kg for rats, dogs, and monkeys, respectively. In all animals tested, the extrarenal clearance was larger than the renal clearance, and neither of the clearances was limited by blood flow. Despite these conditions, garenoxacin showed a good correlation for CL and Vss for allometric interspecies scaling.

Address correspondence to: Hiroyoshi Hayakawa, Department of Drug Safety Research Laboratory, Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1, Shimookui, Toyama, 930-8508, Japan. E-mail: hiroyoshi_hayakawa{at}toyama-chemical.co.jp




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