Transplacental transfer and distribution of pravastatin

Abstract

Objectives Determine the bidirectional transfer of pravastatin across the dually perfused term human placental lobule and its distribution between the tissue, maternal and fetal circuits. Study design The transfer of pravastatin was determined in the Maternal-to-Fetal (n=11) and Fetal-to-Maternal (n=10) directions. Pravastatin was co-perfused with its [3H]-isotope and the marker compound antipyrine (20 μg/mL) and its [14C]-isotope. The concentration of pravastatin in the perfused tissue, the maternal and fetal circuits was determined using liquid scintillation spectrometry. Inside-out vesicles prepared from placental brush border membranes were utilized to investigate the role of efflux transporters in transplacental transfer of pravastatin. Results Pravastatin was transferred from the maternal to the fetal circuit and vise versa. In the Maternal-to-Fetal direction, the distribution of pravastatin at the end of experiment was as follows: 14 ± 5% of the drug was retained by the tissue, 68 ± 5% remained in the maternal circuit, and 18±4% was transferred to the fetal circuit. The normalized transfer of pravastatin (Clearance index) to antipyrine in the Fetal-to-Maternal direction (0.48 ± 0.07) was higher than its transfer in the Maternal-to-Fetal direction (0.36 ± 0.07, p<0.01). Furthermore, pravastatin inhibited the ATP-dependent uptake of the paclitaxel and estrone sulfate. Conclusions The transfer of pravastatin across the dually perfused placental lobule suggests that fetal exposure to pravastatin is plausible. The higher transfer of pravastatin in the Fetal-to-Maternal direction than the reverse as well as its inhibition of the ATP-dependent uptake of [3H]-paclitaxel and [3H]-estrone sulfate strongly suggest the involvement of efflux transporters in decreasing its transfer across the placenta, and support pravastatin favorable pharmacokinetic profile in pregnancy.

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess

“…Indeed, in human first trimester placental explants, pravastatin inhibits insulin-like growth factor 1 receptor function with adverse implications for trophoblast differentiation (39). With regard to the fetus, the levels of pravastatin achieved within the fetal circulation in this current study are unknown, but earlier studies have demonstrated that transfer of pravastatin in ex vivo human placenta occurs albeit to a limited extent (40,41). However, it is of interest to note that we observed no induction of Vegfa expression in Hsd11b2 −/− fetal heart, suggesting that if pravastatin is eliciting direct effects on the fetus, it may be via different pathways.…”

Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia

“…Unlike simvastatin, which is hydrophobic, pravastatin is hydrophilic, meaning it may less readily cross through the placenta to the fetus. 11,13 Cohort studies have shown that administration of lipophilic statins have increased fetal malformation risk; however, hydrophilic statins, including pravastatin, have not been associated with an increased risk. 11 A multicenter randomized controlled trial has been undertaken to examine the effect of oral pravastatin on serum sFlt-1 levels in women with preterm preeclampsia, 14 and a separate prevention trial has also started.…”

Pravastatin to prevent obstetrical complications in women with antiphospholipid syndrome

“…Moreover, it is not dependent on CYP3A metabolism; therefore, there are no clinically relevant pharmacokinetic interactions between pravastatin and CYP3A inhibitors. Additionally, pravastatin is a substrate of placental efflux transporters such as P-glycoprotein and multidrug resistance-associated protein 2 (17,18). Consistent with these characteristics, recent transplacental studies have shown that the drug's ability to cross the placenta was limited and clearance was higher in the fetal-to-maternal direction than the maternal-to-fetal direction (18).…”

“…Additionally, pravastatin is a substrate of placental efflux transporters such as P-glycoprotein and multidrug resistance-associated protein 2 (17,18). Consistent with these characteristics, recent transplacental studies have shown that the drug's ability to cross the placenta was limited and clearance was higher in the fetal-to-maternal direction than the maternal-to-fetal direction (18). The US randomized controlled trial additionally showed that renal clearance of pravastatin is higher in pregnancy compared with in the nonpregnant state, adding uncertainty to the ideal dose with the safest profile to be used in high-risk pregnant women (15).…”