title: Concentrations of the des-F(6)-quinolone garenoxacin in plasma and joint cartilage of immature rats.
abstract: Garenoxacin is a des-F(6)-quinolone with a broad antibacterial spectrum, which has previously been shown to exhibit low chondrotoxicity in juvenile dogs compared with several other quinolones. A study was performed to determine whether the low chondrotoxicity observed in immature rats following garenoxacin treatment could be explained by poor penetration into cartilage tissue. Garenoxacin was orally administered to immature (4- to 5-week-old) Wistar rats as a single dose-or as doses given on 5 consecutive days-of 0 (vehicle), 200, 400, and 600 mg/kg ( n=5 per dose level). Additional groups of rats were orally dosed with 600 mg/kg ofloxacin and ciprofloxacin. One knee joint of each animal (24 h after the last dose) was studied histologically after staining with Toluidine blue. The pharmacokinetics of garenoxacin in plasma (200, 400, and 600 mg/kg) and in knee joint cartilage (200 and 600 mg/kg) was assessed in separate groups of rats ( n=55 per dose level). Concentrations of garenoxacin in plasma and cartilage were measured using an HPLC method. No signs of chondrotoxicity were observed in the immature rats treated with garenoxacin or ciprofloxacin for 5 days at the doses investigated in this study. However, ofloxacin was found to induce cartilage lesions that were typical of those seen for this quinolone. Systemic exposure to garenoxacin increased as a function of dose. Across dose and study day, mean garenoxacin plasma maximum concentration ( C(max)) and area under the concentration-time curve (AUC(tau)) values were in the range 12-26 mg/l and 33-133 mgxh/l, respectively. Garenoxacin C(max) and AUC were similar on days 1 and 5, within each dose, indicating the absence of accumulation or reduction in the systemic exposure. Values determined for T(max) (0.25-1.0 h) and T(1/2) (3.8-6.4 h) of garenoxacin in plasma did not vary with dose or study day. Although peak garenoxacin concentrations in cartilage were between equal levels to and 2.5-fold of those found in plasma, the observed ratios were somewhat lower than those reported for other quinolones, e.g. ofloxacin or sparfloxacin. Since garenoxacin appeared to be well absorbed following oral administration and concentrations in cartilage tended to be higher than those in plasma, it is unlikely that the low chondrotoxicity in comparison with other quinolones is explained by differences in the pharmacokinetics of these compounds.
authors.affiliation: Department of Toxicology, Institute of Clinical Pharmacology and Toxicology, Campus Benjamin Franklin Charité Universitätsmedizin Berlin, Garystrasse 5, 14195, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kastner
authors.forename: Ute
authors.initials: U
authors.lastname: Rahm
authors.forename: Irmela
authors.initials: I
authors.lastname: Baumann-Wilschke
authors.forename: Akintunde
authors.initials: A
authors.lastname: Bello
authors.forename: Ralf
authors.initials: R
authors.lastname: Stahlmann
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002939:Ciprofloxacin / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D015242:Ofloxacin / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013047:Specific Pathogen-Free Organisms
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D002939:Ciprofloxacin; D015242:Ofloxacin; C419689:garenoxacin