Pharmacokinetics and metabolism of single oral doses of trovafloxacin

Trovafloxacin, a new fluoronaphthyridone derivative related to fluoroquinol one antimicrobial drugs, has demonstrated the following characteristics: si gnificant gram-positive and gramnegative activity; significant activity aga inst anaerobes and atypical respiratory pathogens; approximately 11-hour el imination half-life, permitting once-daily administration; and good tissue penetration. Because <10% of an orally administered dose is recovered in ur ine as unchanged drug, the predominant route of trovafloxacin elimination a ppears to be nonrenal. The two studies described in this review examined th e metabolism and excretion of trovafloxacin and compared the time course an d concentrations of trovafloxacin and its metabolites in bile to those in s erum. In the first study, four healthy male volunteers received a single, oral 20 0-mg dose of radiolabeled trovafloxacin. In the second study, three patient s with indwelling nasobiliary tubes received a single 200-mg dose of trovaf loxacin. Samples of blood, urine, bile, and feces were collected. Trovaflox acin in urine and serum was analyzed by high-performance liquid chromatogra phy (HPLC) with ultraviolet (UV) detection and in bile by HPLC-mass spectro scopy (MS). Levels of the N-acetyl metabolite in bile were determined by HP LG/UV/MS. Metabolites in serum, urine, and feces were determined by reverse -phase HPLC/MS, and radioactivity in these samples was assayed by liquid sc intillation counting. In the first study, 63.3% and 23.1% of total radioactivity were recovered i n feces and urine, respectively, with most of the radioactivity in urine in the form of the ester glucuronide metabolite (12.8%) and unchanged trovafl oxacin (5.9%). Unchanged drug, the N-acetyl metabolite, and the N-sulfate o f trovafloxacin accounted for 43.2%, 9.2%, and 3.9%, respectively, of the r adioactivity in feces. In the second study, biliary trovafloxacin concentra tions were highest between 1.5 and in hours postdose, and the maximum conce ntrations ranged from 18.9 to 37.9 mu g/mL. The mean bile:serum ratio of tr ovafloxacin was 14.9, and the biliary concentration of parent drug was high er than that of its N-acetyl metabolite. In both studies, trovafloxacin was well tolerated, with no discontinuations due to adverse events. The pharmacokinetic profile of trovafloxacin in serum was consistent in hea lthy subjects and in individuals who had undergone recent hepatobiliary sur gery. Trovafloxacin is metabolized primarily by the liver, through phase II metabolism (glucuronidation 13.2%, N-acetylation 10.4%, and N-sulfoconjuga tion 4.1%); minimal oxidative metabolism was detected. Renal elimination ac counted for <10% of the administered dose. The high bile to serum ratio and higher trovafloxacin concentrations relative to metabolite concentrations are consistent with nonrenal elimination. These pharmacokinetic and pharmac odynamic results, together with a broad antimicrobial spectrum, long 11-hou r elimination half-life, and low drug-interaction potential, suggest that t rovafloxacin may be particularly appropriate for use in the surgical settin g. (C) 1998 by Excerpta Medica, Inc.