Metabolic disposition of the new fluoroquinolone antibacterial agent DW116 in rats

Abstract

The metabolic disposition of the new fluoroquinolone antibacterial agent DW116 has been studied in Sprague-Dawley rats. The compound was absorbed well and demonstrated excellent oral bioavailability. The plasma kinetic profiles were characterized by monoexponential elimination with an elimination half life of 3-4 hr, The apparent mean total clearance (CI,) and the volume of distribution (V-ss) ranged from 221 +/- 55 to 274 +/- 27 ml/hr/kg and 1.0 +/- 0.1 to 1.5 +/- 0.2 l/kg, respectively, and were independent of dose between 4 and 20 mg/kg levels. The renal (Cl-B) clearance was 64.5 ml/hr/kg and the biliary (Cl-B) clearance was 33.8 ml/hr/kg. The combined value accounted for approximately one-half of the total clearance, indicating that the remaining one-half of the administered dose was eliminated via hepatic clearance. The major metabolite excreted in the bile was identified as the glucuromide ester of parent drug using base-hydrolysis of the conjugate metabolite followed by co-HPLC with standard compound F-19-NMR and LC-MS methods. The mean urinary recoveries of free and total (free plus glucuronide ester) DW116 were 28.6 +/- 2.7% and 36.4 +/- 1.8% of the administered dose and the corresponding biliary recoveries were 14.4 +/- 5.5% and 37.0 +/- 7.6%, respectively. The mass balance study after a single (100mg/kg) oral administration of C-14-DW116 indicated complete recovery of radioactivity over a 7-day period, accounting for approximately 60-70% in feces and 30-40% in urine. C-14-DW116 extensively distributed during a prolonged process into all tissues with a rather slower penetration into the brain, lung, and muscle. The compound also readily crossed the placenta and was transferred to the fetus.