Transplacental transport of paracetamol and its phase II metabolites using the ex vivo placenta perfusion model

Conings, Sigrid; Tseke, Fotini; Broeck, Annick Van den; Qi, Bing; Paulus, Jasmin; Amant, Frédéric; Annaert, Pieter; Calsteren, Kristel Van

doi:10.1016/j.taap.2019.03.004

Cited by 26 publications

(31 citation statements)

References 38 publications

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“…Coefficient from Ex Vivo Cotyledon Perfusion Experiment 2.5.1.1 Placenta Perfusion The study protocol was approved by the ethics review board of the University Hospitals (UZ) Leuven (s54819), Eudra-CT number 2012-004580-51, ClinicalTrials.gov identifier NCT02622802 [43]. The experimental setup and methodology have been published previously [18]. Placentas were perfused in a recirculating (closed-closed) circuit within 30 min after delivery.…”

Section: Estimation Of Placental Permeability and Partitionmentioning

confidence: 99%

“…The transcotyledon passive diffusion clearance (D cot ) was assumed to be equal in both fetal-tomaternal and maternal-to-fetal direction (i.e., no polarity was assumed). Although acetaminophen-glucuronide and acetaminophen-sulphate transfer have been investigated [18], both metabolites were not implemented as verification with in vivo data was not possible. The cotyledon volume was assumed to be 58 mL on average [44].…”

Section: Estimation Of Placental Transfer Parametersmentioning

confidence: 99%

“…Error models (proportional, constant, mixed) were investigated to describe the residual unexplained variability. Simulated concentrations in the maternal and fetal reservoirs were compared to the ex vivo experiment concentrations [18]. Equations where D pl (mL/min) and D cot (mL/min) represent the D pl and transcotyledon passive diffusion clearance, respectively, and V pl (mL) and V cot (mL) represent the placental and cotyledon volumes, respectively.…”

Section: Estimation Of Placental Transfer Parametersmentioning

confidence: 99%

“…2). Three different methods for informing the two unknown parameters of placental transfer (the D pl and partition coefficient) in a PBPK model were evaluated: (i) estimation of the D pl and partition coefficient from the ex vivo cotyledon perfusion experiment [18]; (ii) estimation of the D pl from a previously reported scaling approach via Caco-2 cells while fixing the partition coefficient to a value of 1.0 [2,16]; and (iii) estimation of the D pl from physicochemical properties of the drug (default method implemented in MoBi ® ) while fixing the partition coefficient to a value of 1.0 [3]. Predicted acetaminophen pharmacokinetic profiles were compared to observed data obtained from the umbilical vein at delivery [19].…”

Section: Introductionmentioning

confidence: 99%

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Integration of Placental Transfer in a Fetal–Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus

et al. 2020

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Background and Objective Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal-maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus. Methods An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi ® ]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations. Results Tested approaches to predict placental transfer showed comparable performance, although the ex vivo approach showed highest prediction accuracy. Acetaminophen exposure in maternal venous blood was similar to fetal venous umbilical cord blood. Prediction of fetal acetaminophen clearance indicated that the median molar dose fraction converted to acetaminophen-sulphate and N-acetyl-p-benzoquinone imine was 0.8% and 0.06%, respectively. The predicted mean acetaminophen concentration in the arterial umbilical cord blood was 3.6 mg/L. Conclusion The median dose fraction of acetaminophen converted to its metabolites in the term fetus was predicted. The various placental transfer approaches supported the development of a generic f-m PBPK model incorporating in vivo placental drug transfer. The predicted arterial umbilical cord acetaminophen concentration was far below the suggested postnatal threshold (24.47 mg/L) for ductal closure.

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Section: Estimation Of Placental Permeability and Partitionmentioning

confidence: 99%

Section: Estimation Of Placental Transfer Parametersmentioning

confidence: 99%

Section: Estimation Of Placental Transfer Parametersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Integration of Placental Transfer in a Fetal–Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus

et al. 2020

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“…In a similar way to indomethacin, AA enters the foetal compartment from the maternal side 31 . In contrast, AA neither delayed labour nor constricted foetal PDA before 32 weeks of gestation 32 .…”

Section: Early Closure Of Pdamentioning

confidence: 92%

Early closure mechanisms of the ductus arteriosus in immature infants

et al. 2021

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Aim According to experimental studies, cardiopulmonary distress decreases after closure of patent ductus arteriosus. However, early closure of the ductus using ibuprofen or indomethacin has failed to increase survival without serious morbidity. We review relevant data aiming to define optimal early management strategies that promote early closure of ductus arteriosus without serious adverse effects. Methods Literature in English was searched selectively focusing on the potential of using acetaminophen for early closure of the ductus. Results Prophylactic ibuprofen or indomethacin intended to close the ductus, predisposes infants to ischaemia, bleeding and immune dysfunction. Acetaminophen appears to have a similar efficacy as indomethacin or ibuprofen, and all three dose‐dependently constrict the ductus. Ibuprofen and indomethacin cause non‐specific inhibition of prostaglandin synthesis, while acetaminophen predominantly inhibits prostaglandin E synthesis. Owing to low CYP450 activity in infancy, acetaminophen toxicity has been rarely evident. However, increasing the dosage increases the oxidative stress. We review prophylactic treatments that may increase the safety and efficacy of acetaminophen. These include vitamin A, cysteine and glutamine, and low‐dose corticosteroid supplementation. Conclusion The current challenge is to define a safe perinatal management practice that promotes cardiorespiratory adaptation in immature infants, particularly the seamless closure of the ductus before significant cardiopulmonary distress develops.

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