In vivo pharmacokinetic analyses of placental transfer of three drugs of different physicochemical properties in pregnant rats

Abstract

Although the use of medication during pregnancy is common, information on exposure to the developing fetus and potential teratogenic effects is often lacking. This study used a rat model to examine the placental transfer of three small-molecule drugs with molecular weights ranging from approximately 300 to 800 Da with different physicochemical properties. Time-mated Sprague Dawley (Hsd:SD) rats aged 11–13 weeks were administered either glyburide, rifaximin, or fentanyl at gestational day 15. Maternal blood, placentae, and fetuses were collected at 5 min, 30 min, 1 h, 4 h, 8 h, 24 h, 48 h, and 96 h post-dose. To characterize the rate and extent of placental drug transfer, we calculated several pharmacokinetic parameters such as maximum concentration (Cmax), time to maximum concentration (Tmax), area under the concentration–time curve (AUC), half-life (t1/2), clearance (CL), and volume of distribution (Vd) for plasma, placenta, and fetus tissues. The results indicated showed that fetal exposure was lowest for glyburide, accounting for only 2.2 % of maternal plasma exposure as measured by their corresponding AUC ratio, followed by rifaximin (37.9 %) and fentanyl (172.4 %). The fetus/placenta AUC ratios were found to be 10.7 % for glyburide, 11.8 % for rifaximin, and 39.1 % for fentanyl. These findings suggest that although the placenta acts as a protective shield for the fetus, the extent of protection varies for different drugs and depends on factors such as molecular weight, lipid solubility, transporter-mediated efflux, and binding to maternal and fetal plasma proteins.