Integration of Placental Transfer in a Fetal–Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus
Clinical Pharmacokinetics, ISSN: 1179-1926, Vol: 59, Issue: 7, Page: 911-925
2020
- 41Citations
- 39Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations41
- Citation Indexes41
- 41
- CrossRef5
- Captures39
- Readers39
- 39
Article Description
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.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85079503807&origin=inward; http://dx.doi.org/10.1007/s40262-020-00861-7; http://www.ncbi.nlm.nih.gov/pubmed/32052378; http://link.springer.com/10.1007/s40262-020-00861-7; https://dx.doi.org/10.1007/s40262-020-00861-7; https://link.springer.com/article/10.1007/s40262-020-00861-7
Springer Science and Business Media LLC
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