Clinical trial: modulation of human placental multidrug resistance proteins in cholestasis of pregnancy by ursodeoxycholic acid.
ABSTRACT The effects of ursodeoxycholic acid on human placental bile acids and bilirubin transporters in intrahepatic cholestasis of pregnancy are still undefined.
To evaluate whether ursodeoxycholic acid affects MRP2, MRP3 and MRP4 expression in the placenta.
Forty-three pregnant women were enrolled; fourteen subjects had physiological pregnancies. Intrahepatic cholestasis of pregnancy patients were divided into two groups: (i) 13 received ursodeoxycholic acid (20 mg/kg/day) and (ii) 16 untreated. Total bile acid and bilirubin in serum and cord blood were determined in each subject. Multidrug resistance proteins expression (immunoblot, quantitative real-time PCR) was evaluated in placentas collected at delivery. anova test was used for statistical analysis of data.
Ursodeoxycholic acid administration significantly improved maternal serum bile acid and cord blood bilirubin and bile acid levels. MRP2 protein and RNA expression was significantly increased in placentas from treated patients compared to controls (P < 0.001 and P < 0.01, respectively). MRP3 protein expression was not significantly different between the groups while RNA expression was significantly decreased in treated patients (P < 0.01). MRP4 did not show significant differences between the groups.
Ursodeoxycholic acid administration induces placental MRP2 expression, and reduces bilirubin and bile acid levels in cord blood.
Full-textDOI: · Available from: Antonio Colecchia, Sep 23, 2014
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ABSTRACT: Introduction: Medication of pregnant women is increasingly common in developed countries. Several placental drug transporters have been shown to transfer their substrates from the trophoblast back to the maternal circulation, thus hindering the transplacental passage of xenobiotics and protecting the fetus. However, the expression and activity of drug transporter proteins in the placenta vary during gestation and are tightly regulated by many factors. In addition, their function can be compromised by pathological conditions and/or drug-drug interactions. Areas covered: This article reviews current knowledge on placental drug transporters, their effects on placental pharmacokinetics and the regulatory mechanisms that control their expression and activity. Transcriptional, genetic and epigenetic mechanisms of placental transporter regulation and the drug-drug interactions that modulate transporter activity are described. Physiological and pathological factors that can affect drug transporter expression and function in the placenta are also discussed. Expert opinion: The expression and activity of drug transporter proteins in the placenta vary during gestation and are tightly regulated by many factors. Subsequently, there is a great variability in the expression and function of placental drug transporters both within human populations (interindividual variability) and also during gestation (intraindividual variability). An understanding of the expression and function of placental drug transporters is essential for efficient and safe therapy during pregnancy. There is clearly a need for further preclinical and clinical studies on placental drug transporters, but such investigations must be carefully designed and the resulting data should be evaluated with great caution. This review highlights several methodological aspects that will have to be considered and addressed in order to shed further light on these important issues.Expert Opinion on Drug Metabolism & Toxicology 01/2015; 11(4):1-23. DOI:10.1517/17425255.2015.1005073 · 2.93 Impact Factor
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ABSTRACT: AimIntrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and elevated bile acid concentrations in maternal serum. This is accompanied by an enhanced risk of intrauterine and perinatal complications. High levels of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial etiopathogenesis of ICP. The aim of this study was to further investigate the mechanism accounting for the beneficial effect of oral administration of ursodeoxycholic acid (UDCA), which is the standard treatment, regarding bile acid and PMS homeostasis in the mother-placenta-foetus trio.Methods Using HPLC-MS/MS bile acids and PMS were determined in maternal and foetal serum and placenta. The expression of ABC proteins in placenta was determined by RT-QPCR and immunofluorescence.ResultsIn ICP, markedly increased levels of bile acids (tauroconjugates >glycoconjugates >>unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced levels in foetal serum of bile acids, but not of PMS. UDCA treatment reduced bile acid accumulation in the mother-placenta-foetus trio, but had no significant effect on progesterone and PMS levels. ABCG2 mRNA abundance was increased in placentas from ICP patients vs controls and remained stable following UDCA treatment, despite an apparent further increase in ABCG2.ConclusionsUDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on levels of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high levels of bile acids and PMS during ICP.British Journal of Clinical Pharmacology 08/2014; 79(2). DOI:10.1111/bcp.12480 · 3.69 Impact Factor
Article: Clinical Therapeutics in Pregnancy[Show abstract] [Hide abstract]
ABSTRACT: Most drugs are not tested for use during pregnancy, consequently, labeling, which may include information about fetal safety, includes nothing about dosing, efficacy, or maternal safety. Yet these are concerns of health care providers considering treatment of disease during pregnancy. Therefore, the practitioner treats the pregnant woman with the same dose recommended for use in adults (typically men) or may decide not to treat the disease at all. However, is the choice of not treating a woman during pregnancy better than dealing with the challenges which accompany treatment? This paper, which summarizes metabolic and physiologic changes induced by pregnancy, illustrates that standard adult dosing is likely to be incorrect during pregnancy.BioMed Research International 07/2011; 2011:783528. DOI:10.1155/2011/783528 · 2.71 Impact Factor