[Show abstract][Hide abstract] ABSTRACT: Garenoxacin is a novel quinolone that does not have a fluorine substituent at the C-6 position in the quinoline ring. Garenoxacin or 14C-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.
Drug Metabolism and Disposition 11/2003; 31(11):1409-18. DOI:10.1124/dmd.31.11.1409 · 3.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The articular toxicity of garenoxacin (formerly T-3811 or BMS-284756) was experimentally examined utilizing juvenile beagle dogs. Garenoxacin and two other reference quinolones were administered at intravenous dosages of 30 and 60 mg/kg. Each group consisted of 3 male dogs (Experiment I). Oral dosages of 50 mg/kg of 3 compounds were also given daily to male only and female only groups (Experiment II) over a period of 7 days. We evaluated the articular toxicity of garenoxacin compared to ciprofloxacin and norfloxacin. In Experiment I, no articular toxicity was detected in the 30 mg/kg garenoxacin group. One animal from the 60 mg/kg garenoxacin group developed detectable histopathological lesions in the articular cartilages of the shoulder, elbow and knee joints. In the 30 mg/kg ciprofloxacin group and the 30 and 60 mg/kg norfloxacin groups, histopathological articular cartilage lesions of the shoulder, elbow, carpus, hip, knee and tarsus joints were observed in all of the dogs. The area under the plasma concentration-time curve (AUC0-->infinity) values, after the first dose was administered, for the 30 mg/kg groups given garenoxacin, ciprofloxacin and norfloxacin were 164, 68.1 and 65.7 micrograms.hr/mL, respectively. In Experiment II, the degree of histopathological change was most significant in the ciprofloxacin group, followed by the norfloxacin group, and with comparatively the least changes in the garenoxacin group. The AUC0-->infinity values, obtained after the 6th day of antimicrobial administration, were 202 and 173 micrograms.hr/mL for male and female dogs, respectively, from the 50 mg/kg garenoxacin group. The AUC0-->infinity values for the garenoxacin group after the 6th daily administration were 7.8 to 17.0 times greater for male dogs and 3.8 to 13.2 times greater for female dogs than those obtained from the ciprofloxacin and norfloxacin groups. The concentrations of garenoxacin in the synovia, articular cartilage and the synovialis 4 hr following the last garenoxacin administration were 2.0 to 6.5 times higher for male dogs and 1.5 to 3.3 times higher for female dogs than the antimicrobial levels measured in the ciprofloxacin and norfloxacin groups. As discussed above, although the garenoxacin concentrations in plasma and joint tissue were higher than those for ciprofloxacin and norfloxacin, however, the articular toxicity of garenoxacin was much less than that of the other two antimicrobials.
The Journal of Toxicological Sciences 09/2002; 27(3):219-28. DOI:10.2131/jts.27.219 · 1.29 Impact Factor