Gestational Age-Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics.

Some women take medication during pregnancy to address a variety of clinical conditions. Due to ethical and logistical concerns, it is impossible to determine fetal drug exposure, and therefore fetal risk during pregnancy. Hence alternative approaches need to be developed to predict maternal-fetal drug exposure throughout pregnancy. To do so, we previously developed and verified a maternal-fetal Physiologically Based Pharmacokinetic (m-f-PBPK) model, which can predict fetal exposure to drugs that passively cross the placenta. However, many drugs are actively transported by the placenta (e.g. HIV protease inhibitors). In order to extend our m-f-PBPK model to these actively transported drugs, we determined the gestational-age dependent changes in the protein abundance of placental transporters. Total cellular membrane fractions from first trimester (T1, n=15), second trimester (T2, n=19) and term (n=15) human placentae, obtained from uncomplicated pregnancies, were isolated by ultracentrifugation. Transporter protein abundance was determined by targeted quantitative proteomics using LC-MS/MS. We observed that BCRP and P-gp abundance significantly decreased from T1 to term by 55% and 69%, respectively (per gram of tissue). OATP2B1 abundance significantly decreased from T1 to T2 by 32%. In contrast, OCT3 and OAT4 abundance significantly increased with gestational age (2-fold from T1 to term, 1.6-fold from T2 to term). SERT and NET did not change with gestational age. The abundance of BSEP, MRP1-5, NTCP, OATP1B1, OATP1B3, OCTN1-2, CNT1-3, ENT2, and MATE1 could not be quantified. These data can be incorporated into our m-f-PBPK to predict fetal exposure to drugs which are actively transported across the placenta.