Effects of ivermectin on reproduction and neonatal toxicity in rats

In this study we describe the effects of ivermectin (MK-0933) on the reproduction and neonatal toxicity of several generations of rats. Ivermectin was administered orally at dose levels of 0.05, 0.1, 0.2, 0.4, 1.2 or 3.6 mg/kg body weight/day. An increase in postnatal pup mortality up to approximately day 10 post-partum and a decrease in pup weights in the surviving offspring compared with those of the control groups indicated that ivermectin was toxic to neonatal rats at doses as low as 0.4 mg/kg body weight/day. Cross-fostering of the rats indicated that the neonatal toxicity was related not to in utero exposure but to postnatal exposure through maternal milk. Subsequent studies with tritiated ivermectin administered orally to rats showed that levels of radioactivity in maternal milk were 3-4-fold higher than those in the plasma, which resulted in significantly higher levels of ivermectin in the brain and plasma of nursing offspring. The period of enhanced neonatal sensitivity (up to approximately day 10 post-partum) correlates with increases in the plasma-brain ratios of total radioactivity in offspring from approximately 1 on day 4 post-partum to approximately 3 on day 10 post-partum. This is consistent with the postnatal formation of the blood-brain barrier in the species. In other mammalian species, including humans, sheep and rabbits, the blood-brain barrier is formed pre-natally. Therefore, the neonatal toxicity of ivermectin in rats is probably the result of a combination of excessive exposure through maternal milk and the increased permeability of the blood-brain barrier during the early postnatal period in this species.