METABOLISM AND EXCRETION OF TROVAFLOXACIN, A NEW QUINOLONE ANTIBIOTIC, IN SPRAGUE-DAWLEY RATS AND BEAGLE DOGS - EFFECT OF BILE-DUCT CANNULATION ON EXCRETION PATHWAYS

The excretion and metabolism of trovafloxacin was investigated after a dministration of a single oral dose of [C-14]trovafloxacin to Sprague- Dawley rats and beagle dogs. The bile was the major route of excretion in rats (59% of the dose). Trovafloxacin was extensively metabolized in this species, and only 3% of the dose was excreted unchanged. Glucu ronidation and acetylation were the major metabolic pathways involved in the elimination, and no oxidative metabolites were detected in rats . In dogs, 97.6 and 2.7% of the dose was recovered in feces and urine, respectively, in 72 hr. However, excretion studies in bile duct-cannu lated dogs revealed that 28.2% of the radioactivity was recovered in b ile, whereas 45.6% was in urine. This suggested that bile duct cannula tion had affected the disposition of trovafloxacin. Analysis of bile a nd urine of bile duct-cannulated dogs by LC/MS/MS indicated that glucu ronidation was the major metabolic pathway in dogs as well, Two novel metabolites were identified in the bile of this species, One was confi rmed as a pyrroline analog of trovafloxacin (M7), and the second was t entatively identified as the hydroxycarboxylic acid analog (M6). The d ifferences in metabolism of trovafloxacin in the bile duct-cannulated and noncannulated dogs were investigated by comparison of the metaboli te profiles in urine and feces of these animals. Although the metaboli tes in urine were similar, the extracts of fecal samples obtained from noncannulated animals revealed the presence of N-acetyltrovafloxacin (M3). Incubation of trovafloxacin with cecal contents of dogs under an aerobic conditions suggested the involvement of intestinal microflora in the formation of this metabolite. Metabolite M3 was absent from fec al extracts of bile duct-cannulated dogs, suggesting that surgery had affected the metabolism of trovafloxacin by gut microflora.