Pharmacokinetics and metabolism of single oral doses of trovafloxacin

Trovafloxacin, a new fluoronaphthyridone derivative related to fluoroquinolone antimicrobial drugs, has demonstrated the following characteristics: significant gram-positive and gram-negative activity; significant activity against anaerobes and atypical respiratory pathogens; approximately 11-hour elimination half-life, permitting once-daily administration; and good tissue penetration. Because <10% of an orally administered dose is recovered in urine as unchanged drug, the predominant route of trovafloxacin elimination appears to be nonrenal. The two studies described in this review examined the metabolism and excretion of trovafloxacin and compared the time course and concentrations of trovafloxacin and its metabolites in bile to those in serum. In the first study, four healthy male volunteers received a single, oral 200-mg dose of radiolabeled trovafloxacin. In the second study, three patients with indwelling nasobiliary tubes received a single 200-mg dose of trovafloxacin. Samples of blood, urine, bile, and feces were collected. Trovafloxacin in urine and serum was analyzed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection and in bile by HPLC-mass spectroscopy (MS). Levels of the N-acetyl metabolite in bile were determined by HPLC/UV/MS. Metabolites in serum, urine, and feces were determined by reverse-phase HPLC/MS, and radioactivity in these samples was assayed by liquid scintillation counting. In the first study, 63.3% and 23.1% of total radioactivity were recovered in feces and urine, respectively, with most of the radioactivity in urine in the form of the ester glucuronide metabolite (12.8%) and unchanged trovafloxacin (5.9%). Unchanged drug, the N-acetyl metabolite, and the N-sulfate of trovafloxacin accounted for 43.2%, 9.2%, and 3.9%, respectively, of the radioactivity in feces. In the second study, biliary trovafloxacin concentrations were highest between 1.5 and 10 hours postdose, and the maximum concentrations ranged from 18.9 to 37.9 μg/mL. The mean bile:serum ratio of trovafloxacin was 14.9, and the biliary concentration of parent drug was higher 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 healthy subjects and in individuals who had undergone recent hepatobiliary surgery. Trovafloxacin is metabolized primarily by the liver, through phase II metabolism (glucuronidation 13.2%, N-acetylation 10.4%, and N-sulfoconjugation 4.1%); minimal oxidative metabolism was detected. Renal elimination accounted 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 pharmacodynamic results, together with a broad antimicrobial spectrum, long 11-hour elimination half-life, and low drug-interaction potential, suggest that trovafloxacin may be particularly appropriate for use in the surgical setting.