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(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 36 Cl-(R,S)-ornidazole in murine tissues. After injection of 36 Cl-(R,S)-α- 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 α-chlorohydrin were twice as rapid in mice as in rats. In mice, α-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)-α-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)-α-chlorohydrin in vitro. [ABSTRACT FROM AUTHOR]

Abstract Background A major event in the post-meiotic development of male germ cells is the formation of the acrosome. This process can be perturbed in C57BL/6 mice by administration of the small molecule miglustat (N-butyldeoxynojirimycin, NB-DNJ). The miglustat-treated mice produce morphologically abnormal spermatozoa that lack acrosomes and are poorly motile. In C57BL/6 mice, miglustat can be used to maintain long-term reversible infertility. In contrast, when miglustat was evaluated in normal men, it did not affect spermatogenesis. To gain more insight into this species difference we have now evaluated the reproductive effects of miglustat in rabbits, in multiple mouse strains and in interstrain hybrid mice. Methods Male mice of 18 inbred strains were administered miglustat orally or via miniosmotic pumps. Rabbits were given the compound in their food. Fourth-generation interstrain hybrid mice, bred from C57BL/6 and FVB/N mice (which differ in their response to miglustat), also received the drug. Data on fertility (natural mating), sperm motility and morphology, acrosome status, and serum drug levels were collected. Results In rabbits the drug did not induce aberrations of sperm shape or motility, although the serum level of miglustat in rabbits far exceeded the level in C57BL/6 mice (8.4 μM and 0.5 μM, respectively). In some strains of the Swiss and Castle lineages of inbred mice miglustat did not cause infertility, severe morphological sperm aberrations or reduced sperm motility. In these strains miglustat only had milder effects. However, miglustat strongly disturbed acrosome and sperm nucleus development in AKR/J and BALB/c mice and in a number of C57BL/6-related strains. The consequences of drug administration in the interstrain hybrid mice were highly variable. Judging by the number of grossly abnormal spermatozoa, these genetically heterogeneous mice displayed a continuous range of intermediate responses, distinct from either of their parental strains. Conclusion The effects of miglustat on spermatogenesis in mice are strain-dependent, while in rabbits the drug is ineffective. Evaluation of interstrain hybrid mice indicated that the sensitivity of spermatogenesis to miglustat is a quantitative trait. These studies pave the way for identifying the genetic factors underlying the strain/species differences in the effect of miglustat.

Reports that the European Academy of Andrology will present prizes to the best two articles published in the 'International Journal of Andrology' in 2002.