Universitas Indonesia Conferences, Asian Federation for Pharmaceutical Sciences (AFPS) 2019

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Mother-to-Fetal Transfer Profiles of Statins in Rats
Tomohiro Nishimura

Last modified: 2019-09-05


Purpose: HMG-CoA reductase inhibitors (statins) are contraindicated for the risk of fetal growth retardation in pregnant women. It has, however, been reported that pravastatin is little toxic in human fetus and can be effective for preeclampsia. The purpose of this study was to clarify relationship between adverse fetal effect and fetal transfer in statins. Methods: Statins were administrated into pregnant Sprague-Dawley rats at gestational day of 18.5 by intravenous infusion for 4 hrs, and maternal and fetal plasma concentration was measured by LC-MSMS. Relationship between the reported fetal toxicity of statins and the measured fetal-to-maternal plasma concentration ratio, octanol-water distribution coefficient (log D), protein binding and inhibition constants (Ki) for breast cancer resistance protein (BCRP) has been analyzed. Results and Discussion: The reported fetal toxicity of simvastatin was relatively higher than that of other statins. Fetal-to-maternal plasma concentration ratio of rosuvastatin, atorvastatin, pravastatin, simvastatin acid, lovastatin, simvastatin was 0.033, 0.061, 0.11, 0.20, 0.20, and 0.59, respectively. These results suggest that fetal toxicities of statin are related with their fetal transfer since simvastatin indicated the highest transfer among the tested statins. The fetal-to-maternal plasma concentration ratio was correlated with the values of log D, but it was not correlated with plasma protein binding ratio and Ki value for BCRP. Conclusions: Our results implied that adverse fetal effects of statins are related with their fetal transfer. Although several statins are substrates of BCRPs, our data showed that fetal-to-maternal concentration ratio of statins is correlated with their hydrophobicity and that role of BCRP in the fetal transfer is less important at least in rats.