title: The effect of (R,S)-ornidazole on the fertility of male mice and the excretion and metabolism of 36Cl-(R,S)-ornidazole and 36Cl-(R,S)-alpha-chlorohydrin in male mice and rats.
abstract: (R,S)-Ornidazole, an effective antifertility agent for male rats at 400 mg/kg/day, was ineffective at this dose in male mice and at 1000 mg/kg/day caused neural effects. The compound was not excreted unchanged and more polar metabolites and Cl- were detected in 0-8 h urine following a single injection (400 mg/kg). In 8-24 h urine even these metabolites and most Cl ion were absent, indicating rapid metabolism of ornidazole. There was no organ specific accumulation of 36Cl-(R,S)-ornidazole in murine tissues. After injection of 36Cl-(R,S)-alpha-chlorohydrin, another antifertility agent in the rat but not the mouse, there was also no tissue-specific accumulation of radioactivity in the reproductive tract of either species. Urinary excretion rates of alpha-chlorohydrin were twice as rapid in mice as in rats. In mice, alpha-chlorohydrin was the major urinary metabolite, but in the rat metabolites included Cl-, 3-chlorolactate (BCLA) at 5 and 10 h and BCLA only at 24 h. BCLA was the major metabolite detected in most tissues at 10 and 24 h. In the rat cauda (but not caput) epididymidis the glycolytic inhibitor 3-chlorolactaldehyde was present at 5 h (but not 10 h), indicative of early metabolism. These results demonstrate a greater metabolism and excretion of putative antifertility agents in the mouse than the rat, lowering the amount of effective inhibitor circulating in the animal, which may explain why (R,S)-alpha-chlorohydrin and (R,S)-ornidazole are ineffective in this species at the dosages and injection times used, despite their spermatozoa being sensitive to inhibition by (R,S)-alpha-chlorohydrin in vitro.
authors.affiliation: Institute of Reproductive Medicine of the University Münster, Münster, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Bone
authors.forename: A R
authors.initials: AR
authors.lastname: Jones
authors.forename: T G
authors.initials: TG
authors.lastname: Cooper
mesh_terms: D000563:Amebicides / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D002713:Chlorine; D002728:Chlorohydrins / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D005298:Fertility / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D009950:Ornidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000652:urine; D011868:Radioisotopes; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000563:Amebicides; D002728:Chlorohydrins; D011868:Radioisotopes; D002713:Chlorine; D009950:Ornidazole