Reproductive study. II: Prenatal and postnatal development study with candoxatril in Sprague-Dawley rats.
Candoxatril, a prodrug for candoxatrilat, a selective inhibitor of neutral endopeptidase, was administered orally to groups of 24 female rats at doses of 0, 120, 400 or 1200 mg/kg/day from gestation day 6 to lactation day 21 to assess effects on pre- and postnatal development of F1 offspring. All dams were allowed to litter and to raise their F1 offspring until lactation day 21. The F1 offspring were examined for postnatal developmental indices, reflex behaviors and memory. A functional observational battery (FOB) was also conducted. A marked increase in spontaneous activity of the dams was observed in all candoxatril-treated groups. Maternal body weight gain was decreased in the 400 and 1200 mg/kg/day groups during the treatment periods. No significant differences were found for reproductive parameters. The male and female pups in the 1200 mg/kg/day group had significantly lower body weights beginning on postnatal days 21 and 14, respectively, through to the end of the study. There were no drug-related effects on pre- and postnatal developmental indices, FOB, sensory function tests or memory test. The no observed adverse effect levels were 120 and 400 mg/kg/day for the F0 dams and F1 offspring, respectively.