Metabolism of droloxifene in the CD-1 mouse, Fischer-344 rat and cynomolgus monkey.

1. The fate of [14C]droloxifene, a novel non-steroidal anti-oestrogen, was studied following oral administration to the CD-1 mouse, F-344 rat and Cynomolgus monkey. 2. Most of the radioactivity was primarily excreted in the faeces and urine was the minor route of excretion. 3. Droloxifene was extensively metabolized in all three species, primarily by two metabolic pathways; glucuronidation of unchanged droloxifene and oxidative metabolism, presumably by cytochrome P450. 4. In mouse, oxidative metabolism followed by conjugation played a significant role in the elimination of droloxifene. An unusual diglucuronide of 4-hydroxydroloxifene was also identified in this species. 5. In rat, glucuronidation and oxidative metabolism were significant, whereas in monkey glucuronidation of droloxifene was the predominant pathway of elimination.

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 administration of a single oral dose of [14C]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. Glucuronidation 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-cannulated dogs revealed that 28.2% of the radioactivity was recovered in bile, whereas 45.6% was in urine. This suggested that bile duct cannulation had affected the disposition of trovafloxacin. Analysis of bile and urine of bile duct-cannulated dogs by LC/MS/MS indicated that glucuronidation was the major metabolic pathway in dogs as well. Two novel metabolites were identified in the bile of this species. One was confirmed as a pyrroline analog of trovafloxacin (M7), and the second was tentatively identified as the hydroxycarboxylic acid analog (M6). The differences in metabolism of trovafloxacin in the bile duct-cannulated and noncannulated dogs were investigated by comparison of the metabolite profiles in urine and feces of these animals. Although the metabolites 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 anaerobic conditions suggested the involvement of intestinal microflora in the formation of this metabolite. Metabolite M3 was absent from fecal extracts of bile duct-cannulated dogs, suggesting that surgery had affected the metabolism of trovafloxacin by gut microflora.