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Publication

Transplacental passage of paracetamol and its metabolites

Book - Dissertation

It is estimated that over 90% of pregnant women take over-the-counter or prescription medication. Nevertheless data on transplacental transfer or fetal effects of prenatal drug exposure are lacking, even for the most frequently administered drugs during pregnancy like paracetamol (PCM).PCM is one of the most commonly used over-the-counter medicines and is considered the safest painkiller for pregnant women. In Europe, 50-60% of pregnant women uses PCM at least once during their pregnancy. Recently, epidemiological studies have shown an association between fetal exposure to PCM and neurodevelopmental problems (ADHD, autism) in a dose- and duration-dependent manner. Furthermore, studies indicate that PCM intake during pregnancy and particularly during the first and second trimester is associated with higher occurrence of cryptorchidism, wheezing and asthma in children. Yet, it is unknown whether these developmental problems are caused by the PCM intake or by the underlying problem for which PCM was taken.The general aim of this PhD project was (a) to improve the understanding of transplacental transport of PCM and its Phase II metabolites, PCM sulfate (PCM-S) and PCM glucoronate (PCM-G) and (b) to improve the understanding of the influence of PCM on ATP-binding cassette (ABC) transporters and metabolic enzymes present in the placental barrier.First, an ex vivo human placenta perfusion model was established and validated. In the second part, this human ex vivo placenta perfusion model was used to investigate the transplacental transfer of PCM and its metabolites. The maternal-to-fetal (M-F) and fetal-to-maternal (F-M) transplacental transfer of PCM, PCM-S and PCM-G was determined at concentrations correlating with the therapeutic maximum plasma concentration (Cmax) and with the therapeutic average steady state concentration (Css) in normal clinical use.Antipyrine, a small molecule that passes the placenta by passive diffusion, was used as a reference compound. Since PCM showed the same transfer profile as antipyrine, we concluded that PCM crosses the placenta by passive diffusion. When perfusions were performed with Cmax concentration of PCM, therapeutic concentrations were reached at the fetal side.PCM-S and PCM-G passed the placenta slower than PCM. F-M transport of PCM-S and PCM-G was significantly slower than M-F transfer. Apart from the molecular characteristics and flow-limitation that determine the transfer rate in case of passive diffusion, a potential involvement of transporters was hypothesized.Furthermore, during placenta perfusions with PCM-S and PCM-G slight conversion to PCM was observed, which appeared to be the result of desulfation in the placenta.In the third part, the influence of PCM on ABC transporters and metabolic enzymes present in the placental barrier was investigated. The effect of therapeutic and toxic concentrations of PCM on the expression of BCRP, MRP1, MRP2, MRP3, MRP5, P-gp transporters and CYP3A4 and CYP2E1 enzymes was examined in human primary trophoblast cells. The Caco-2 cell model was used to investigate the correlation between the changes on mRNA level and protein activity. Moreover, the transport mechanism of PCM and its effect on P-gp and MRP activity was investigated in the Caco-2 model, even as the effect of PCM-S and PCM-G on MRP activity.We confirmed that PCM is transported by passive transcellular diffusion. After exposure of the primary trophoblast cells to PCM, an overall downregulation was seen for BCRP and MRP3, while an upregulation was observed for MRP1/2/5 and CYP2E1 on mRNA level. For P-gp an upregulation was seen at therapeutic concentrations, while a downregulation was seen after exposure to toxic concentrations.In the Caco-2 cells, indeed the MRP1/3/5 and MRP2 activity increased after 48/60 h incubation with PCM. PCM had an inhibitory effect on the MRP transporters in the Caco-2 cells which was shown by a significantly reduced efflux of carboxy-dichlorofluorescein (CDF) through MRP2 and MRP1/3/5, while on the other hand, PCM-S and PCM-G had no effect on the MRP function in Caco-2 cells.In conclusion, PCM and its metabolites pass the placental barrier in both directions. Transfer from the F-M circulation is slower than from the M-F circulation, and transfer of PCM-G and PCM-S is slower than PCM transfer. The transport mechanism for PCM is passive transcellular diffusion. For the transfer of the metabolites, a combination of flow-limitation and higher molecular weight could explain the slower transfer, although involvement of a transporter cannot be excluded. Furthermore, PCM is able to alter the expression and activity of ABC transporters. However, the clinical impact of these modifications on the placental transfer of co-administered drugs still needs to be investigated.
Publication year:2017
Accessibility:Closed