注射用右旋兰索拉唑家兔胚胎-胎仔发育毒性比较及伴随毒代与组织分布

目的：研究注射用右旋兰索拉唑对孕兔胚胎-胎仔发育的影响。方法：孕兔于妊娠第6~18天分别给予静脉注射用右旋兰索拉唑3.6，12，36 mg·kg^-1，qd。另设兰索拉唑和左旋兰索拉唑（36 mg·kg^-1）作为消旋和左旋对照，环磷酰胺（10 mg·kg^-1）作为阳性对照，溶媒对照采用氯化钠注射液，第29天处死解剖。观察并记录给药前后孕兔一般症状，处死后，观察母兔生殖状态与胎仔发育情况。于首、末次给药进行伴随毒代采血，解剖时取组织样本，采用LC-MS/MS测定样本内药物浓度。结果：与溶媒对照组相比，右旋兰索拉唑中、高剂量组、消旋、左旋对照组孕兔厌食、体质量下降明显。消旋、左旋和阳性对照组给药后期个别孕兔出现流产。率转换后，右旋高剂量组、消旋、左旋对照组胎仔活胎率显著低于溶媒对照组。胎仔骨骼检查中，右旋高剂量组、消旋和左旋对照组的部分种类骨骼缺失数量，显著高于溶媒对照组。伴随毒代结果可知，右旋兰索拉唑在孕兔体内达峰迅速，代谢较快，未见蓄积。组织分布研究表明右旋兰索拉唑在母体内广泛分布，无特殊脏器亲和，易通过胎盘屏障。结论：右旋高剂量（36 mg·kg^-1）家兔体内表现出一定的母体毒性和胚胎-胚仔发育毒性，右旋中剂量（12 mg·kg^-1）仅表现出母体毒性。

Comparison of embryo-fetal development toxicity of R-(+)-lansoprazole and toxicokinetics in rabbits

OBJECTIVE To investigate the effects of R-(+)-lansoprazole for injection on development of embryo-fetal rabbits.METHODS Pregnant rabbits were intravenously administered R-(+)-lansoprazole (3.6 mg·kg^-1, 12 mg·kg^-1,36 mg·kg^-1) for 13 days from GD6 to GD18 once a day. S-(-)-lansoprazole control group (36 mg·kg^-1), lansoprazole control group (36 mg·kg^-1), positive control group (10 mg·kg^-1) and solvent control group were also assigned. Cesarean section for pregnant rabbits was performed at GD29. Pregnant rabbits' clinical manifestation should be observed and recorded before and after dosing. After execution, pregnant rabbits' reproductive status and fetal development situation were investigated. Concomitant toxicokinetics and tissue distribution were investigated at GD6 and GD18, blood samples were collected in TK group. Tissues were collected from pregnant rabbits and fetus rabbits at GD29. All the blood samples and tissues were analyzed by LC-MS/MS.RESULTS Compared with solvent control group, R-(+)-lansoprazole groups (12, 36 mg·kg^-1), S-(-)-lansoprazole, lansoprazole control group (36 mg·kg^-1) showed significant anorexia and weight loss. Pregnant rabbit abortion occurred in S-(-)-lansoprazole control group, lansoprazole control group and positive control group. The results showed that high dose group and equivalent dose of control group had significantly lower live birth rates than the solvent control group. High dose group, equivalent dose of control group and positive control group had significantly increased bone loss than solvent control group. Concomitant toxicokinetics showed that R-(+)-lansoprazole metabolized rapidly in vivo. There was no drug accumulation. Tissue distribution showed that R-(+)-lansoprazole could easily enter embryo body through placenta membrane. R-(+)-lansoprazole widely distributed in the pregnant rabbits and fetus, and had no special affinity organ.CONCLUSION R-(+)-lansoprazole (36 mg·kg^-1) has toxicities to pregnant and embryo-fetal rabbits, and R-(+)-lansoprazole (12 mg·kg^-1) only has toxicities to pregnant rabbits.