In silico modelling for transplacental transfer of morphine in an ex vivo human cotyledon perfusion system

Transplacental properties of drugs are important for the well-being of fetuses. However, in vivo data on the transplacental effects of most drugs are rare due to ethical issues and technical challenges. Hence, ex vivo placenta cotyledon perfusion experiments have been used to investigate the transplacental properties since the 1960s. Recently there have been some efforts in developing in silico models to investigate subtle properties of placental transfer, such as drug-drug interaction (DDI). Morphine is a pain relief medication that may be administered in pregnant women in labour. The compound readily penetrates the placental membrane barrier through passive diffusion and may lead to a risk of fetal exposure. In this study, an in silico model is constructed to reproduce the pharmacokinetic profiles of morphine in maternal and fetal blood observed from an ex vivo perfusion experiment conducted by a research group in the University of Toronto (1). Our model is based on a recently published in silico model for ex vivo cotyledon transfer of metformin (2) that consists of multiple compartments to represent different components of the ex vivo system, as well as the interfaces between the maternal and fetal circulations in the cotyledon. As morphine has different physicochemical and pharmacokinetic properties to metformin, the parameters of the model are refit according to the experiments of Kopecky et al (1) for morphine. Since the structure of the in silico model may be applied to many similar transplacental experiments of other drugs, we also performed Latin Hypercube Sampling analysis to investigate the interplay between parameters as part of the parameter analysis. The work is to report our findings in model construction and parameter analysis.


  1. Kopecky EA, Simone C, Knie B, Koren G. Transfer of morphine across the human placenta and its interaction with naloxone. Life Sciences. 1999 Oct;65(22):2359–71.
  2. Kurosawa K, Chiba K, Noguchi S, Nishimura T, Tomi M. Development of a pharmacokinetic model of transplacental transfer of metformin to predict in vivo fetal exposure. Drug Metab Dispos [Internet]. 2020 Jan 1 [cited 2022 Jan 4]; Available from: