REPRODUCTIVE TOXICITY OF CABERGOLINE IN MICE, RATS, AND RABBITS

Cabergoline, a new dopaminergic ergot derivative,vith potent long-last ing prolactin (PRL)-lowering properties, was assessed using standard r eproductive studies in the mouse, rat, and rabbit with oral administra tion. Because of the compound's pharmacologic activity, several aspect s remain incompletely explored in the rat, in which prolactin is the l uteotrophic hormone. A fertility study in female rats was possible onl y at very low doses (0.5, 1, and 2 mu g/kg/d) because higher doses com pletely inhibited implantation. In male rats no adverse effects were s een on male reproductive performance or on the offspring at doses up t o 320 mu g/kg/d given for 10 weeks prior to mating with untreated fema les. In a developmental toxicity study in rats treated from day 6 to d ay 15 of gestation at doses (6.25, 12.5, and 25 mu g/kg/d) not exceedi ng the active dose for inhibition of egg nidation (ED(50) = 25 mu g/kg ), a high incidence of total litter loss occurred as a reflection of i nhibition of egg nidation at the highest dose, but embryofetal develop ment was not impaired in litters reaching term. An exploratory study a t 30 or 1000 mu g/kg/d with treatment from day 5 of gestation or later demonstrated that cabergoline did not affect the maintenance of pregn ancy at 30 mu g/kg/d given from day 7 or later, or at 1000 mu g/kg/d g iven from day 9. Doses of 500, 2000, and 8000 mu g/kg/d (treatment fro m day 6 to day 15 of gestation) did not inhibit egg nidation in mice a nd showed no adverse effects on intrauterine development. Doses rangin g from 5 to 8000 mu g/kg/d administered from day 6 to day 18 of gestat ion in the rabbit were associated with maternal effects, including a r eduction in body weight gain and food and water intake starting from 5 00 mu g/kg/d and increased reactivity at the highest doses (4000 and 8 000 mu g/kg/d). Effects on intrauterine development were restricted to a reduction in mean fetal and placental weights at 4000 and 8000 mu g /kg/d. In peri- and postnatal studies in rats (treatment from day 15 o r 17 of gestation to weaning) cabergoline did not affect fetal develop ment and parturition up to 100 mu g/kg/d, but strongly inhibited milk secretion starting from 10 mu g/kg/d, thus leaving unexplored the post natal phase at higher doses. When neonatal rats (born from untreated d ams) were treated directly with cabergoline at 10, 30, and 90 mu g/kg/ d from day 7 to 13 after birth, treatment was well tolerated up to the highest dose tested (90 mu g/kg/d). It was concluded that cabergoline did not impair fertility in the male rat, was not teratogenic in mice and rabbits, did not affect the latter phase of gestation or parturit ion in the rat, and was not toxic when administered directly to neonat al rats. (C) 1996 Elsevier Science Inc.