Transfer of uremic solutes across the human term placenta: An ex vivo study in the dual-side perfused cotyledon

Schakenraad, L.; Es, Manuilova; Meerman, J.J.; Broek, P.H.H. van den; Hove, Hedwig van; Drongelen, J. van; Eliesen, Gaby A M; Rüssel, Frans G. M.; Greupink, Rick

doi:10.1016/j.placenta.2020.12.015

Cited by 4 publications

(6 citation statements)

References 52 publications

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“…GC coupled with triple quadrupole mass spectrometry (QqQ-MS/MS) has further been utilized to assess prenatal exposure to diverse environmental organic pollutants, such as polycyclic aromatic hydrocarbons, organophosphorus pesticides, polybrominated diphenyl ethers, and others, using non-invasive biological samples (meconium and placenta) [ 65 ]. LC-MS/MS was also effectively used to obtain more knowledge about the placental transfer of uremic solutes across the human placenta [ 66 ]. GC coupled to tandem MS was applied to detect polybrominated diphenyl ethers and polychlorinated biphenyls in the placentas of mothers with gestational diabetes mellitus [ 67 ].…”

Section: Resultsmentioning

confidence: 99%

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Kotta-Loizou,

Pritsa,

Antasouras

et al. 2024

Diseases

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Background: The placenta exerts a crucial role in fetus growth and development during gestation, protecting the fetus from maternal drugs and chemical exposure. However, diverse drugs and chemicals (xenobiotics) can penetrate the maternal placental barrier, leading to deleterious, adverse effects concerning fetus health. Moreover, placental enzymes can metabolize drugs and chemicals into more toxic compounds for the fetus. Thus, evaluating the molecular mechanisms through which drugs and chemicals transfer and undergo metabolism across the placental barrier is of vital importance. In this aspect, this comprehensive literature review aims to provide a holistic approach by critically summarizing and scrutinizing the potential molecular processes and mechanisms governing drugs and chemical transfer and metabolism across the placental barrier, which may lead to fetotoxicity effects, as well as analyzing the currently available experimental methodologies used to assess xenobiotics placental transfer and metabolism. Methods: A comprehensive and in-depth literature review was conducted in the most accurate scientific databases such as PubMed, Scopus, and Web of Science by using relevant and effective keywords related to xenobiotic placental transfer and metabolism, retrieving 8830 published articles until 5 February 2024. After applying several strict exclusion and inclusion criteria, a final number of 148 relevant published articles were included. Results: During pregnancy, several drugs and chemicals can be transferred from the mother to the fetus across the placental barrier by either passive diffusion or through placental transporters, resulting in fetus exposure and potential fetotoxicity effects. Some drugs and chemicals also appear to be metabolized across the placental barrier, leading to more toxic products for both the mother and the fetus. At present, there is increasing research development of diverse experimental methodologies to determine the potential molecular processes and mechanisms of drug and chemical placental transfer and metabolism. All the currently available methodologies have specific strengths and limitations, highlighting the strong demand to utilize an efficient combination of them to obtain reliable evidence concerning drug and chemical transfer and metabolism across the placental barrier. To derive the most consistent and safe evidence, in vitro studies, ex vivo perfusion methods, and in vivo animal and human studies can be applied together with the final aim to minimize potential fetotoxicity effects. Conclusions: Research is being increasingly carried out to obtain an accurate and safe evaluation of drug and chemical transport and metabolism across the placental barrier, applying a combination of advanced techniques to avoid potential fetotoxic effects. The improvement of the currently available techniques and the development of novel experimental protocols and methodologies are of major importance to protect both the mother and the fetus from xenobiotic exposure, as well as to minimize potential fetotoxicity effects.

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Section: Resultsmentioning

confidence: 99%

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Kotta-Loizou,

Pritsa,

Antasouras

et al. 2024

Diseases

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“…closed maternal circuit/closed fetal circuit, maternal circuit flow 12 mL/min, fetal circuit flow 6 mL/min, duration of perfusion 180 min) we consider experiments successful when fluid loss from the fetal circuit is less than 3 mL/h, that the fetal-to-maternal transfer of the high molecular weight compound FITC-dextran is low (ratio approximately 0.01) and the maternal-to-fetal antipyrine transfer ratio is high (>0.8). At the flow rates we operate, antipyrine concentrations are usually equal in both circuits after approximately 120 min of perfusion) ( Eliesen, 2017 , Eliesen, 2020 , Freriksen, 2018 , Schakenraad, 2021 ) .…”

Section: Methodsmentioning

confidence: 99%

Placental transfer of tofacitinib in the ex vivo dual-side human placenta perfusion model

Eliesen,

Fransen,

van Hove

et al. 2024

Current Research in Toxicology

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“…To study the transplacental transfer of doravirine, we performed ex vivo dual-side placenta perfusions in a closed–closed configuration, in both maternal-to-fetal (MTF) and fetal-to-maternal (FTM) directions ( n = 4 each), as described previously [ 22 ] (see electronic supplementary material [ESM]-1). In short, the fetal (6 mL/min) and maternal (12 mL/min) circulation of an intact cotyledon were re-established upon delivery in the laboratory.…”

Section: Methodsmentioning

confidence: 99%

“…Ex vivo human placenta perfusion experiments in closed–open configuration, representative of sink conditions to measure clearance, have been used to estimate placental transfer for integration in PBPK models [ 15 , 20 , 36 ]. To investigate the impact of perfusion experiment configuration, we also performed perfusion experiments in a closed–open configuration in MTF ( n = 3) and FTM ( n = 3) direction, as previously described [ 15 , 22 ]. We subsequently estimated the intrinsic placental transfer parameters with an adjusted mechanistic placenta model.…”

Section: Methodsmentioning

confidence: 99%

“…To study the transplacental transfer of doravirine, we performed ex vivo dual-side placenta perfusions in a closed-closed configuration, in both maternal-to-fetal (MTF) and fetal-to-maternal (FTM) directions (n = 4 each), as described previously [22] (see electronic supplementary material [ESM]-1). In short, the fetal (6 mL/min) and Doravirine is a first-line drug for patients living with HIV that is commonly prescribed in high-income countries because it has a favorable side effect profile, is not a perpetrator of drug-drug interactions, and has good efficacy [4].…”

Section: Ex Vivo Human Placenta Perfusion Experimentsmentioning

confidence: 99%

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Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

et al. 2022

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Background and Objective Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling. Methods Ex vivo placenta perfusions were performed in a closed–closed configuration, in both maternal-to-fetal and fetal-to-maternal directions ( n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration ( C trough ) values were compared with the target (0.23 mg/L) derived from in vivo exposure–response analysis. Results A decrease of 55% in maternal doravirine area under the plasma concentration–time curve (AUC) 0–24h was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM C trough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure. Conclusion Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01127-0.

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Transfer of uremic solutes across the human term placenta: An ex vivo study in the dual-side perfused cotyledon

Cited by 4 publications

References 52 publications

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Placental transfer of tofacitinib in the ex vivo dual-side human placenta perfusion model

Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

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