Developmental toxicity of meglumine antimoniate and transplacental transfer of antimony in the rat

Abstract

Meglumine antimoniate (MA), a pentavalent antimonial (SbV) drug, has been used for the treatment of leishmaniases for over half a century but there is almost no data on its safety and kinetics during pregnancy. This study was undertaken to investigate the developmental toxicity of MA as well as the transplacental transfer of antimony (Sb) in rats. Wistar rats (approximately 20 per group) were treated subcutaneously (s.c.) with MA (0, 75, 150, 300 mg SbV/(kg BW day)) during pregnancy (days 1-20). An untreated control group was evaluated as well. Caesarean sections were performed on day 21 and implantations, living and dead fetuses, and resorptions were recorded. Fetuses were weighed and fixed in Bouin's solution and one-third of each litter was examined for soft-tissue anomalies. The remaining fetuses were cleared and stained with Alizarin red S for skeleton evaluation. No adverse effect of MA on the mothers was noted at any dose level. No embryotoxicity was observed at the lowest dose but, at the highest dose, MA increased embryolethality, reduced fetal weight and augmented the occurrence of some soft-tissue and skeleton variations. Therefore, the no-observed-adverse-effect level for MA-induced embryotoxicity was 75 mg SbV/(kg BW day). In a separate group of rats treated with 300 mg SbV/(kg BW day) s.c. during whole pregnancy, blood (0.2 mL) was taken from the tail vein 1, 2, 4, 6, 12 and 24 h after treatment on day 1 and thereafter every other day immediately before drug injection. Blood was also taken from fetuses removed on day 21, 24h after the last injection of MA. Blood levels of Sb were determined by ICP-MS and results showed that most of administered Sb was eliminated rapidly (in less than 6 h), but nadir blood concentrations increased gradually during treatment from 1 to 2 microg/g, 24h after the first dose, up to approximately 38 microg/g after the 20th dose. Levels of Sb in fetal blood were as high as 10-15 microg/g, i.e. approximately 30% their mothers' nadir levels near term. These findings indicated that repeated administration of MA during gestation led to an accumulation of Sb in mothers and fetuses.