Chiral Transplacental Pharmacokinetics of Fexofenadine: Impact of P-Glycoprotein Inhibitor Fluoxetine Using the Human Placental Perfusion Model.

PURPOSE: Fexofenadine is a well-identified in vivo probe substrate of P-glycoprotein (P-gp) and/or organic anion transporting polypeptide (OATP). This work aimed to investigate the transplacental pharmacokinetics of fexofenadine enantiomers with and without the selective P-gp inhibitor fluoxetine. METHODS: The chiral transplacental pharmacokinetics of fexofenadine-fluoxetine interaction was determined using the ex vivo human placenta perfusion model (n = 4). In the Control period, racemic fexofenadine (75 ng of each enantiomer/ml) was added in the maternal circuit. In the Interaction period, racemic fluoxetine (50 ng of each enantiomer/mL) and racemic fexofenadine (75 ng of each enantiomer/mL) were added to the maternal circulation. In both periods, maternal and fetal perfusate samples were taken over 90 min. RESULTS: The (S)-(-)- and (R)-(+)-fexofenadine fetal-to-maternal ratio values in Control and Interaction periods were similar (~0.18). The placental transfer rates were similar between (S)-(-)- and (R)-(+)-fexofenadine in both Control (0.0024 vs 0.0019 min-1) and Interaction (0.0019 vs 0.0021 min-1) periods. In both Control and Interaction periods, the enantiomeric fexofenadine ratios [R-(+)/S-(-)] were approximately 1. CONCLUSIONS: Our study showed a low extent, slow rate of non-enantioselective placental transfer of fexofenadine enantiomers, indicating a limited fetal fexofenadine exposure mediated by placental P-gp and/or OATP2B1. The fluoxetine interaction did not affect the non-enantioselective transplacental transfer of fexofenadine. The ex vivo placental perfusion model accurately predicts in vivo placental transfer of fexofenadine enantiomers with remarkably similar values (~0.17), and thus estimates the limited fetal exposure.

Rivaroxaban transfer across the dually perfused isolated human placental cotyledon.

OBJECTIVE: The purpose of this study was to determine the rate and extent of rivaroxaban transfer across the term human placenta and determine whether passive diffusion was the primary mechanism involved in this transfer. STUDY DESIGN: The transplacental pharmacokinetics of rivaroxaban was determined with the ex-vivo placenta perfusion model. Rivaroxaban was added to the maternal or fetal circulation only (250 ng/mL). Additional experiments were conducted under equilibrative conditions with the addition of rivaroxaban to both the maternal and fetal circulations (250 ng/mL). Rivaroxaban concentrations were measured with the use of liquid chromatography-tandem mass spectrometry. RESULTS: There was rapid transfer of rivaroxaban across the human placenta in both the maternal-to-fetal and fetal-to-maternal directions, as evidenced by transfer ratios of 0.69 (interquartile range, 0.58-0.73; n = 5) and 0.69 (interquartile range, 0.67-0.71; n = 2), respectively, after 3 hours. Under equilibrative conditions (n = 2), rivaroxaban concentrations remained relatively constant, which suggests that rivaroxaban crosses the placenta down a concentration gradient. CONCLUSION: This is the first direct evidence of rivaroxaban transfer across the term human placenta from both the mother-to-fetus and fetus-to-mother directions. Our results document that unbound rivaroxaban rapidly crosses the placental barrier via passive diffusion. However, because rivaroxaban is highly bound to plasma proteins (up to 95%), this suggests that the amount of unbound drug that may reach the fetus is likely much lower. Additional studies will need to explore its safety before administering rivaroxaban to a pregnant woman.

Asking the right questions to ascertain early childhood secondhand smoke exposures.

Secondhand smoke is associated with a myriad of adverse health outcomes. Therefore, it is essential for clinicians to ask precise questions about exposures, particularly for children. We present 4 questions that incorporate several locations of exposure and provide a more comprehensive account of children's smoke exposures than maternal smoking alone.

Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta.

OBJECTIVE: To assess the transplacental pharmacokinetics at term of the oral thrombin inhibitor, dabigatran, and its prodrug, dabigatran etexilate mesylate, to estimate fetal drug exposure. METHODS: Placentae were obtained with informed consent after cesarean delivery of healthy term pregnancies in Toronto, Ontario, Canada. The transplacental transfer of dabigatran and dabigatran etexilate mesylate was separately assessed using the ex vivo dual perfusion of an isolated human placental cotyledon. Dabigatran, at a concentration of 35 ng/mL, was added to the maternal circulation at the start of the experimental phase. Maternal and fetal samples were taken throughout the preexperimental (1 hour) and experimental (3 hours) phases for measurement of dabigatran and markers of placental viability. Separate placenta perfusions with dabigatran etexilate mesylate were conducted at an initial maternal concentration of 3.5 ng/mL. Dabigatran and dabigatran etexilate mesylate were measured using liquid chromatography-tandem mass spectrometry. RESULTS: There was slower transfer of dabigatran compared with antipyrine from the maternal-to-fetal circulation, because the median fetal-to-maternal concentration ratio was 0.33 (interquartile range 0.29-0.38) after 3 hours (n=3). The prodrug, dabigatran etexilate mesylate, had limited placental transfer as characterized by a fetal-to-maternal ratio of 0.17 (interquartile range 0.15-0.17) after 3 hours (n=3). Placental viability markers for all perfusions were within normal ranges. CONCLUSION: This report provides direct evidence of the transfer of dabigatran and its prodrug across the term human placenta from the mother to the fetus. From a clinical perspective, these data suggest that, pending further study, dabigatran should not be used for anticoagulation of pregnant women, because the drug may have an adverse effect on fetal blood coagulation.

The detection and quantification of ethyl glucuronide in placental tissue and placental perfusate by headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry.

BACKGROUND: Ethyl glucuronide (EtG) is arising as a promising biomarker of heavy prenatal alcohol exposure, however its transfer across the human placenta is still unclear and is currently being investigated using the ex vivo placental perfusion model. This model allows for sampling from placental tissue and placental perfusate, which is a surrogate to plasma. OBJECTIVE: To develop a method for detecting and quantifying EtG in placental perfusate and tissue using headspace solid-phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry (GC-MS). METHODS: A method was optimized by manipulation of the following components to attain the highest peak counts for the quantifying ions of EtG and its deuterated internal standard on the mass spectrum: cartridges used for solid phase extraction, injection method, derivatizing agent, pre-injection parameters, SPME fiber, GC ramp speed, and GC column flow. RESULTS: The final method utilized involved solid phase extraction of standards via UCT CleanScreen Cartridges, derivatization with heptafluorobutyric acid, and introduction into the GC via HS-SPME with adsorption to a polydimethylsiloxane fiber. The method has improved sensitivity over other methods that quantify EtG in blood using GC-MS, with detection limits of 1.6 ng/mL and 13.7 ng/g for placental perfusate and tissue, respectively. The method was applied to samples collected from the fetal reservoir during the ex vivo placental perfusion model and EtG was detected in the fetal circulation after 20 minutes of perfusion, indicating transfer of EtG. CONCLUSIONS: The present method is sensitive and can be used to quantify EtG transfer during ex vivo placental perfusion experiments.

Insulin glargine safety in pregnancy: a transplacental transfer study.

OBJECTIVE: Insulin glargine (Lantus) is an extended-action insulin analog with greater stability and duration of action than regular human insulin. The long duration of action and decreased incidence of hypoglycemia provide potential advantages for its use in pregnancy. However, the placental pharmacokinetics of insulin glargine have not been studied. Therefore, the objective of this study was to determine whether insulin glargine crosses the human placenta using the human perfused placental lobule technique. RESEARCH DESIGN AND METHODS: Placentae were obtained with informed consent after elective cesarean section delivery of noncomplicated term pregnancies. Insulin glargine, at a therapeutic concentration of 150 pmol/l (20 microU/ml) was added to the maternal circulation. Additional experiments were carried out at insulin glargine concentrations 1,000-fold higher than therapeutic levels (150, 225, and 300 nmol/l). A subsequent perfusion for which the maternal circuit remained open and insulin glargine was continuously infused at 150 pmol/l was completed for further confirmation of findings. The appearance of insulin glargine in the fetal circulation was analyzed by a chemiluminescence immunoassay. RESULTS: Results from perfusions carried out at therapeutic concentrations (150 pmol/l) of insulin glargine showed no detectable insulin glargine in the fetal circuit. After perfusion with very high insulin glargine concentrations of 150, 225, and 300 nmol/l, the rate of transfer remained low at 0.079 +/- 0.01, 0.14, and 0.064 pmol . min(-1) . g tissue(-1), respectively. CONCLUSIONS: Insulin glargine, when used at therapeutic concentrations, is not likely to cross the placenta.