Effects of Sertraline and Fluoxetine on P-Glycoprotein at Barrier Sites: In Vivo and In Vitro Approaches

Kapoor, Amita; Iqbal, Majid; Petropoulos, Sophie; Ho, Hay Lam; Gibb, William; Matthews, Stephen G.

doi:10.1371/journal.pone.0056525

Cited by 38 publications

(25 citation statements)

References 31 publications

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“…We have previously determined that in the mouse, placental expression of P-gp declines with gestation while P-gp in the fetal BBB increases [12, 19]; as such we chose mid-gestation (GD15.5) as the time-point to investigate the influence of PolyI:C on P-gp function in these blood-barrier tissues. In both cohorts, [ 3 H]digoxin (50 µg/kg and 1 µCi/animal), a specific P-gp substrate, was injected directly into the tail vein, and dams (GD15.5) were euthanized 1h later by isoflurane overdose [12, 14, 19-21]. Maternal blood was collected via cardiac puncture and plasma was separated for analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Maternal blood was collected via cardiac puncture and plasma was separated for analysis. ‘Fetal-units’ (∼2-5/litter arbitrarily selected) comprising the fetus, amniotic fluid and intact fetal membranes, but not the placenta, were weighed at the time of dissection [12, 14, 19-21]. Considering that the amniotic fluid and fetal membranes contain substrate that has traversed the placenta from maternal circulation, substrate accumulation in the ‘fetal-unit’ provides an index of net transplacental transfer.…”

Section: Methodsmentioning

confidence: 99%

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Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Bloise

Petropoulos

Iqbal

et al. 2017

Cell Physiol Biochem

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Background/Aims: Viral infection during pregnancy is known to affect the fetal brain. The toll-like receptor (TLR)-3 is a pattern recognition receptor activated by viruses known to elicit adverse fetal neurological outcomes. The P-glycoprotein (P-gp) efflux transporter protects the developing fetus by limiting the transfer of substrates across both the placenta and the fetal blood-brain barrier (BBB). As such, inhibition of P-gp at these blood-barrier sites may result in increased exposure of the developing fetus to environmental toxins and xenobiotics present in the maternal circulation. We hypothesized that viral exposure during pregnancy would impair P-gp function in the placenta and in the developing BBB. Here we investigated whether the TLR-3 ligand, polyinosinic:polycytidylic acid (PolyI:C), increased accumulation of one P-gp substrate in the fetus and in the developing fetal brain. Methods: Pregnant C57BL/6 mice (GD15.5) were injected (i.p.) with PolyI:C (5 mg/kg or 10 mg/kg) or vehicle (saline). [³H]digoxin (P-gp substrate) was injected (i.v.) 3 or 23h post-treatment and animals were euthanized 1h later. Maternal plasma, ‘fetal-units’ (fetal membranes, amniotic fluid and whole fetus), and fetal brains were collected. Results: PolyI:C exposure (4h) significantly elevated maternal plasma IL-6 (P<0.001) and increased [³H]digoxin accumulation in the fetal brain (P<0.05). In contrast, 24h after PolyI:C exposure, no effect on IL-6 or fetal brain accumulation of P-gp substrate was observed. Conclusion: Viral infection modeled by PolyI:C causes acute increases in fetal brain accumulation of P-gp substrates and by doing so, may increase fetal brain exposure to xenobiotics and environmental toxins present in the maternal circulation.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Bloise

Petropoulos

Iqbal

et al. 2017

Cell Physiol Biochem

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“…Second, the grouping of drugs to transporter substrates and inhibitors was made by the authors based on individual research papers. The list of substrates and inhibitors may therefore have been incomplete and interpretation challenging due to the numerous methods used in assessment of drug transporters and conflicting data in the literature …”

Section: Discussionmentioning

confidence: 99%

Placental transporter‐mediated drug interactions and offspring congenital anomalies

Ellfolk

Tornio

Niemi

et al. 2020

Brit J Clinical Pharma

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Aims: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are efflux transporters expressed in the placenta, limiting their substrates from reaching the foetus. Our aim was to investigate if concomitant prenatal exposure to several substrates or inhibitors of these transporters increases the risk of congenital anomalies. Methods:The national Drugs and Pregnancy database, years 1996-2014, was utilized in this population-based birth cohort study. In the database, the Medical Birth Register, the Register on Induced Abortions, the Malformation register and the Register on Reimbursed Drug Purchases have been linked. The University of Washington Metabolism and Transport Drug Interaction Database was used to identify substrates and inhibitors of P-gp and BCRP. We included singleton pregnancies ending in birth or elective termination of pregnancy due to foetal anomaly. Known teratogens were excluded. We identified women exposed 1 month before pregnancy or during the first trimester to P-gp/BCRP polytherapy (n = 21 186); P-gp/breast cancer resistance protein monotherapy (n = 97 906); non-P-gp/BCRP polytherapy (n = 78 636); and unexposed (n = 728 870). We investigated the association between the exposure groups and major congenital anomalies using logistic regression adjusting for several confounders. Results:The prevalence of congenital anomalies was higher in the P-gp/BCRP polytherapy group (5.5%) compared to the P-gp/BCRP monotherapy (4.7%, OR 1.13; 95% CI 1.05-1.21), the non-P-gp/BCRP polytherapy (4.9%, OR 1.14; 95% CI 1.06-1.22), and to the unexposed groups (4.2%, OR 1.23; 95% CI 1.15-1.31). Conclusion:The results suggest a role of placental transporter-mediated drug interactions in teratogenesis. K E Y W O R D Sbirth defects, drug transporters, P-glycoprotein, placenta, pregnancy

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“…Sertraline has potential for drug‐drug interaction with drugs metabolized by CYP2D6, for which it is a weak to moderate inhibitor; additionally, sertraline is a weak inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYPBA4 . There is also potential for drug‐drug interaction involving P‐glycoprotein, as sertraline is both a possible substrate of P‐glycoprotein and a potent inhibitor of its function …”

mentioning

confidence: 99%

“…7 There is also potential for drug-drug interaction involving P-glycoprotein, as sertraline is both a possible substrate of P-glycoprotein and a potent inhibitor of its function. 8,9 The maximum recommended sertraline dose for US adult patients is 200 mg/day. 1 Sertraline is considered generally safe and well tolerated, and the benefit-risk profile is well known.…”

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confidence: 99%

A Thorough QT Study to Evaluate the Effects of a Supratherapeutic Dose of Sertraline on Cardiac Repolarization in Healthy Subjects

Abbas

Riley

LaBadie

et al. 2019

Clinical Pharm in Drug Dev

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The effect of steady‐state supratherapeutic sertraline (Zoloft) on QT interval was assessed in a single‐center, randomized, 3‐way crossover, double‐blind, placebo‐ and moxifloxacin‐controlled thorough QT study. Healthy adults received sertraline 400 mg/day, moxifloxacin 400 mg, and placebo, with a washout period (≥14 days) between treatments. A 12‐lead electrocardiogram was recorded in triplicate before dosing and at selected time points up to 72 hours after dosing. Analysis of covariance using a mixed‐effect model with sequence, period, treatment, time, and treatment‐by‐time interaction as fixed effects; subject within sequence as a random effect; and baseline QT corrected for heart rate using Fridericia formula (QTcF) as a covariate was conducted. A 90% confidence interval for the least squares (LS) mean difference in QTcF between active treatment and placebo was computed for each postdose time point. Exposure‐response was assessed using linear mixed‐effect modeling. Fifty‐four subjects were enrolled. Over 24 hours after dosing, the LS mean difference in QTcF for sertraline versus placebo ranged from 5.597 milliseconds to 9.651 milliseconds. The upper bound of the 90% confidence interval for the LS mean difference exceeded a predefined 10‐millisecond significance threshold at the 4‐hour postdose time point only (LS mean, 9.651 milliseconds [90% confidence interval, 7.635‐11.666]). In the exposure‐response analysis, QTcF values increased significantly with increasing sertraline concentration (slope = 0.036 milliseconds/ng/mL; P < .0001). Predicted change from baseline in QTcF at therapeutic maximum plasma sertraline concentration was 3.57 milliseconds. This thorough QTc study demonstrated a positive signal for QTc prolongation for sertraline at the steady‐state 400‐mg/day dose.

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Effects of Sertraline and Fluoxetine on P-Glycoprotein at Barrier Sites: In Vivo and In Vitro Approaches

Cited by 38 publications

References 31 publications

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Placental transporter‐mediated drug interactions and offspring congenital anomalies

A Thorough QT Study to Evaluate the Effects of a Supratherapeutic Dose of Sertraline on Cardiac Repolarization in Healthy Subjects

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