Abstract
Transport of drugs across biological barriers has been a subject of study for decades. The discovery and characterization of proteins that confer the barrier properties of endothelia and epithelia, including tight junction proteins and membrane transporters belonging to the ATP-binding cassette (ABC) and Solute Carrier (SLC) families, represented a significant step forward into understanding the mechanisms that govern drug disposition. Subsequently, numerous studies, including both pre-clinical approaches and clinical investigations, have been carried out to determine the influence of physiological and pathological states on drug disposition. Importantly, there has been increasing interest in gaining a better understanding of drug disposition during pregnancy, since epidemiological and clinical studies have demonstrated that the use of medications by pregnant women is significant and this condition embodies a series of significant anatomical and physiological modifications, particularly at excretory organs and barrier sites (e.g., placenta, breast) expressing transporter proteins which influence pharmacokinetics. Currently, most of the research in this field has focused on the expression profiling of transporter proteins in trophoblasts and endothelial cells of the placenta, regulation of drug-resistance mechanisms in disease states and pharmacokinetic studies. However, little attention has been placed on the influence that the cerebrovascular dysfunction present in pregnancy-related disorders, such as preeclampsia, might exert on drug disposition in the mother’s brain. This issue is particularly important since recent findings have demonstrated that preeclamptic women suffer from long-term alterations in the integrity of the blood-brain barrier (BBB). In this review we aim to analyze the available evidence regarding the influence of pregnancy on the expression of transporters and TJ proteins in brain endothelial cells, as well the mechanisms that govern the pathophysiological alterations in the BBB of women who experience preeclampsia. Future research efforts should be focused not only on achieving a better understanding of the influence of preeclampsia-associated endothelial dysfunction on drug disposition, but also in optimizing the pharmacological treatments of women suffering pregnancy-related disorders, its comorbidities and to develop new therapies aiming to restore the integrity of the BBB.
Highlights
Worldwide, there has been an increase in the number of prescribed and over-the-counter medications taken by pregnant women (Mitchell et al, 2011; Beyene and Beza, 2018; Navaro et al, 2018)
Pharmacokinetic studies carried out in animal models and human suggest that exposure to drugs is reduced in pregnancy since there is an increase in both the renal glomerular filtration rate and hepatic metabolism mediated by isoforms of cytochrome P450 enzymes and uridine 5 -phosphate glucuronosyltransferases (Pariente et al, 2016; Koren and Pariente, 2018)
This study demonstrated that inhibition of vascular endothelial growth factor (VEGF) receptor tyrosine kinase activity reversed the effect elicited by the treatment with preeclamptic plasma, suggesting that VEGF could be involved in modulating vascular permeability
Summary
There has been an increase in the number of prescribed and over-the-counter medications taken by pregnant women (Mitchell et al, 2011; Beyene and Beza, 2018; Navaro et al, 2018). The above-mentioned statistics are significant since pregnancy is a physiological condition associated with anatomical and physiological modifications capable of influencing the disposition of drugs, including increased blood volume, enhanced basal metabolism, and modified hormone levels, among others. Pharmacokinetic studies carried out in animal models and human suggest that exposure to drugs is reduced in pregnancy since there is an increase in both the renal glomerular filtration rate (thereby increasing renal elimination) and hepatic metabolism mediated by isoforms of cytochrome P450 enzymes and uridine 5 -phosphate glucuronosyltransferases (Pariente et al, 2016; Koren and Pariente, 2018). The expression and activity of transporters involved in drug disposition appears to be modified in excretory organs (Hebert et al, 2008) in a similar fashion to that observed with metabolizing enzymes
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