scholarly journals Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine

2016 ◽  
Vol 60 (9) ◽  
pp. 5563-5572 ◽  
Author(s):  
Martina Ceckova ◽  
Josef Reznicek ◽  
Zuzana Ptackova ◽  
Lukas Cerveny ◽  
Fabian Müller ◽  
...  
Keyword(s):  
Mdck Cells ◽  
Antiretroviral Drugs ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Glycoprotein P ◽  
Term Placenta ◽  
Placental Transport ◽  
Hiv Positive Women ◽  
Drug Efflux Transporters

ABSTRACTLamivudine is one of the antiretroviral drugs of choice for the prevention of mother-to-child transmission (MTCT) in HIV-positive women. In this study, we investigated the relevance of drug efflux transporters P-glycoprotein (P-gp) (MDR1 [ABCB1]), BCRP (ABCG2), MRP2 (ABCC2), and MATE1 (SLC47A1) for the transmembrane transport and transplacental transfer of lamivudine. We employedin vitroaccumulation and transport experiments on MDCK cells overexpressing drug efflux transporters,in situ-perfused rat term placenta, and vesicular uptake in microvillous plasma membrane (MVM) vesicles isolated from human term placenta. MATE1 significantly accelerated lamivudine transport in MATE1-expressing MDCK cells, whereas no transporter-driven efflux of lamivudine was observed in MDCK-MDR1, MDCK-MRP2, and MDCK-BCRP monolayers. MATE1-mediated efflux of lamivudine appeared to be a low-affinity process (apparentKmof 4.21 mM andVmaxof 5.18 nmol/mg protein/min in MDCK-MATE1 cells). Consistent within vitrotransport studies, the transplacental clearance of lamivudine was not affected by P-gp, BCRP, or MRP2. However, lamivudine transfer across dually perfused rat placenta and the uptake of lamivudine into human placental MVM vesicles revealed pH dependency, indicating possible involvement of MATE1 in the fetal-to-maternal efflux of the drug. To conclude, placental transport of lamivudine does not seem to be affected by P-gp, MRP2, or BCRP, but a pH-dependent mechanism mediates transport of lamivudine in the fetal-to-maternal direction. We suggest that MATE1 might be, at least partly, responsible for this transport.

scholarly journals Raltegravir Permeability across Blood-Tissue Barriers and the Potential Role of Drug Efflux Transporters

2015 ◽  
Vol 59 (5) ◽  
pp. 2572-2582 ◽  
Author(s):  
M. Tozammel Hoque ◽  
Olena Kis ◽  
María F. De Rosa ◽  
Reina Bendayan
Keyword(s):  
Human Blood ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Cancer Resistance ◽  
Concurrent Administration ◽  
Glycoprotein P ◽  
Blood Brain ◽  
Drug Efflux Transporters

ABSTRACTThe objectives of this study were to investigate raltegravir transport across several blood-tissue barrier models and the potential interactions with drug efflux transporters. Raltegravir uptake, accumulation, and permeability were evaluatedin vitroin (i) P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1), or MRP4-overexpressing MDA-MDR1 (P-gp), HEK-ABCG2, HeLa-MRP1, or HEK-MRP4 cells, respectively; (ii) cell culture systems of the human blood-brain (hCMEC/D3), mouse blood-testicular (TM4), and human blood-intestinal (Caco-2) barriers; and (iii) rat jejunum and ileum segments using anin situsingle-pass intestinal perfusion model. [3H]Raltegravir accumulation by MDA-MDR1 (P-gp) and HEK-ABCG2-overexpressing cells was significantly enhanced in the presence of PSC833 {6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-l-valine-cyclosporine}, a P-gp inhibitor, or Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1′,2′:1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], a BCRP inhibitor, suggesting the inhibition of a P-gp- or BCRP-mediated efflux process, respectively. Furthermore, [3H]raltegravir accumulation by human cerebral microvessel endothelial hCMEC/D3 and mouse Sertoli TM4 cells was significantly increased by PSC833 and Ko143. In human intestinal Caco-2 cells grown on Transwell filters, PSC833, but not Ko143, significantly decreased the [3H]raltegravir efflux ratios. In rat intestinal segments, [3H]raltegravirin situpermeability was significantly enhanced by the concurrent administration of PSC833 and Ko143. In contrast, in the transporter inhibition assays, raltegravir (10 to 500 μM) did not increase the accumulation of substrate for P-gp (rhodamine-6G), BCRP ([3H]mitoxantrone), or MRP1 [2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)] by MDA-MDR1 (P-gp)-, HEK-ABCG2-, or HeLa-MRP1-overexpressing cells, respectively. Our data suggest that raltegravir is a substrate but not an inhibitor of the drug efflux transporters P-gp and BCRP. These transporters might play a role in the restriction of raltegravir permeability across the blood-brain, blood-testicular, and blood-intestinal barriers, potentially contributing to its low tissue concentrations and/or low oral bioavailability observed in the clinic setting.

scholarly journals P-glycoprotein Mediated Efflux Modulators of Plant Origin: A Short Review

2016 ◽  
Vol 11 (5) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Nuno Silva ◽  
Lígia Salgueiro ◽  
Ana Fortuna ◽  
Carlos Cavaleiro
Keyword(s):  
Short Review ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Plant Origin ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Plant Compounds ◽  
Drug Efflux Transporters

Drug efflux transporters such as P-glycoprotein (P-gp) help maintain cellular homeostasis but are also major contributors to the development of multidrug resistance (MDR) phenomena. Since P-gp was associated with MDR, several compounds showing potential to inhibit this transporter have been identified. Particular attention has been given to natural products, namely those of plant origin, looking for highly effective and safe P-gp inhibitors with little to no interaction with other cellular or metabolic processes. Here we abridge several examples of plant compounds from distinct classes, polyketides, lignans, anthraquinones, coumarins, alkaloids, mono- and sesqui-terpenes, steroids and limonoids, which have shown the ability to modulate in vitro or in vivo the P-gp activity.

scholarly journals Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 813 ◽  
Author(s):  
Dimitrios Vagiannis ◽  
Eva Novotna ◽  
Adam Skarka ◽  
Sarah Kammerer ◽  
Jan-Heiner Küpper ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Lung Tumor ◽  
Mrna Level ◽  
Efflux Transporters ◽  
Drug Candidate ◽  
Drug Efflux ◽  
Cellular Models ◽  
Drug Efflux Transporters

Ensartinib (X-396) is a promising tyrosine kinase inhibitor currently undergoing advanced clinical evaluation for the treatment of non-small cell lung cancer. In this work, we investigate possible interactions of this promising drug candidate with ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 biotransformation enzymes (CYPs), which play major roles in multidrug resistance (MDR) and pharmacokinetic drug-drug interactions (DDIs). Accumulation studies showed that ensartinib is a potent inhibitor of ABCB1 and ABCG2 transporters. Additionally, incubation experiments with recombinant CYPs showed that ensartinib significantly inhibits CYP3A4 and CYP2C9. Subsequent molecular docking studies confirmed these findings. Drug combination experiments demonstrated that ensartinib synergistically potentiates the antiproliferative effects of daunorubicin, mitoxantrone, and docetaxel in ABCB1, ABCG2, and CYP3A4-overexpressing cellular models, respectively. Advantageously, ensartinib’s antitumor efficiency was not compromised by the presence of MDR-associated ABC transporters, although it acted as a substrate of ABCB1 in Madin-Darby Canine Kidney II (MDCKII) monolayer transport assays. Finally, we demonstrated that ensartinib had no significant effect on the mRNA-level expression of examined transporters and enzymes in physiological and lung tumor cellular models. In conclusion, ensartinib may perpetrate clinically relevant pharmacokinetic DDIs and modulate ABCB1-, ABCG2-, and CYP3A4-mediated MDR. The in vitro findings presented here will provide a valuable foundation for future in vivo investigations.

scholarly journals Expressional Study of Permeability glycoprotein (P-gp) and Multidrug Resistance Protein 1 (MRP-1) in Drug-Resistant Mesial Temporal Lobe Epilepsy

2021 ◽  
pp. 1-31
Author(s):  
Mandeep Kaur ◽  
◽  
Tulika Gupta ◽  
Mili Gupta ◽  
Parampreet S. Kharbanda ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Mesial Temporal Lobe Epilepsy ◽  
Efflux Transporters ◽  
P Value ◽  
Drug Efflux ◽  
Drug Resistant ◽  
Glycoprotein P ◽  
Mesial Temporal Lobe ◽  
Drug Efflux Transporters

About 30% of epileptic patients do not react to anti-epileptic drugs leading to refractory seizures. The pathogenesis of drug-resistance in Mesial Temporal Lobe Epilepsy (MTLE) is not completely understood. Increased activity of drug-efflux transporters might be involved, resulting in subclinical concentrations of the drug at the target site. The major drug-efflux transporters are permeability glycoprotein (P-gp) and multidrug-resistance associated protein-1 (MRP-1). The major drawback so far is the expressional analysis of transporters in equal numbers of drug-resistant epileptic tissue and age-matched non-epileptic tissue. We have studied these two transporters in the sclerotic hippocampal tissues resected from the epilepsy surgery (n=15) and compared their expression profile with the tissues resected from non-epileptic autopsy cases (n=15). Statistically significant over expression of both P-gp (p-value <0.0001) and MRP-1 (p-value 0.01) at gene and protein levels was found in the MTLE cases. The fold change of P-gp was more pronounced than MRP-1. Immunohistochemistry of patient group showed increased immunoreactivity of P-gp at blood brain barrier and increased reactivity of MRP-1 in parenchyma. The results were confirmed by confocal immunofluorescence microscopy. The study demonstrated that P-gp in association with MRP-1 might be responsible for the multi-drug resistance in epilepsy

Effect of drug efflux transporters on placental transport of antiretroviral agent abacavir

2015 ◽  
Vol 57 ◽  
pp. 176-182 ◽  
Author(s):  
Zuzana Neumanova ◽  
Lukas Cerveny ◽  
Susan L. Greenwood ◽  
Martina Ceckova ◽  
Frantisek Staud
Keyword(s):  
Efflux Transporters ◽  
Drug Efflux ◽  
Placental Transport ◽  
Drug Efflux Transporters

scholarly journals Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug–Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo

2021 ◽  
Vol 22 (21) ◽  
pp. 11936
Author(s):  
Dimitrios Vagiannis ◽  
Youssif Budagaga ◽  
Anselm Morell ◽  
Yu Zhang ◽  
Eva Novotná ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Biotransformation Enzymes ◽  
Clinical Investigations ◽  
Nsclc Patients ◽  
Drug Efflux Transporters

Tepotinib is a novel tyrosine kinase inhibitor recently approved for the treatment of non-small cell lung cancer (NSCLC). In this study, we evaluated the tepotinib’s potential to perpetrate pharmacokinetic drug interactions and modulate multidrug resistance (MDR). Accumulation studies showed that tepotinib potently inhibits ABCB1 and ABCG2 efflux transporters, which was confirmed by molecular docking. In addition, tepotinib inhibited several recombinant cytochrome P450 (CYP) isoforms with varying potency. In subsequent drug combination experiments, tepotinib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCB1 and ABCG2 overexpression, respectively. Remarkably, MDR-modulatory properties were confirmed in ex vivo explants derived from NSCLC patients. Furthermore, we demonstrated that anticancer effect of tepotinib is not influenced by the presence of ABC transporters associated with MDR, although monolayer transport assays designated it as ABCB1 substrate. Finally, tested drug was observed to have negligible effect on the expression of clinically relevant drug efflux transporters and CYP enzymes. In conclusion, our findings provide complex overview on the tepotinib’s drug interaction profile and suggest a promising novel therapeutic strategy for future clinical investigations.

Combating HIV-1 by Targeting Drug Efflux Transporters on the Macrophage Reservoir

2021 ◽  
Author(s):  
◽  
Ying Mu ◽  
Keyword(s):  
Viral Suppression ◽  
Macrophage Polarization ◽  
Antiretroviral Drugs ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
M1 Macrophage ◽  
And Function ◽  
Hiv 1 ◽  
Transporter Expression ◽  
Drug Efflux Transporters

Introduction. HIV-1 eradication has not been achieved so far due to the existence of the cellular reservoir in which the virus can reside and replicate even under antiretroviral drug therapy (ART). Infected macrophages, which represent a long-term viral reservoir have been shown to lead to viral rebound independently. In response to the environmental stimuli, macrophages can be polarized into different phenotypes: the pro-inflammatory M1 and the anti-inflammatory M2. Tobacco smoking and alcohol drinking, which are prevalent among people who are living with HIV-1, have been shown to promote HIV-1 progression and decrease the efficacy of antiretroviral drugs. A commonly used macrolide antibiotic azithromycin (AZM) has been shown to shift macrophage polarization in a murine macrophage cell line. In the previous research, we found that drug efflux transporters expressed differently between macrophage phenotypes. In this dissertation, we examined the effects of CSC, ethanol exposure, and AZM on the expression and function of clinically relevant drug efflux transporters, viral suppression of antiretroviral drugs, and macrophage polarization. Methods. The human monocytic cell lines U937 and the U1 cell line, which is derived from HIV-1 infected U937, were used and polarized to the M1 and M2 macrophages. Cells with the treatment of CSC, ethanol, and AZM were harvested for downstream analysis including macrophage polarization, oxidative stress, cytokine production, transporter expression and function, and viral suppression. Cells treated with IKK-16, an inhibitor of the NF-κB signaling pathway, were harvested for the analysis of transporter expression and function. Protease inhibitor lopinavir (LPV) was used to suppress viral replication and the intracellular LPV was measured using LC-MS/MS. Results. Cigarette smoke condensate (CSC) and AZM shifted M1 macrophage polarization to M2 while having minimal effects on the M2 macrophage polarization. Inhibiting macrophage subset-specific transporters significantly increased intracellular antiretroviral drug (ARV) concentrations and drug efficacy. Neither CSC nor ethanol had any effect on the transporter inhibition-mediated viral reduction. AZM modulated the expression of major drug efflux transporters in both macrophage subsets and increased intracellular ARV concentration in M2 macrophages. NF-κB and JNK are involved in the M1 macrophage polarization shift and NF-κB was also shown to regulate major transporter expression. Conclusion. Modulating the expression and function of macrophage subset-specific transporter expression can increase intracellular ARV concentration and drug efficacy of viral suppression. Targeting subset-specific transporter may be an effective way to increase intracellular ARV concentration in the macrophage reservoir.

scholarly journals THE MODULATION OF DRUG EFFLUX TRANSPORTER BY CURCUMIN IN MCF7 BREAST CANCER CELLS AFTER REPEATED EXPOSURE OF ENDOXIFEN AND ESTRADIOL

2018 ◽  
Vol 10 (1) ◽  
pp. 102
Author(s):  
Robby Hertanto ◽  
Wilson Bastian ◽  
Paramita . ◽  
Melva Louisa
Keyword(s):  
Breast Cancer ◽  
Cell Viability ◽  
Mrna Expression ◽  
Rna Extraction ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Mcf7 Cells ◽  
Total Rna ◽  
P Glycoprotein ◽  
Drug Efflux Transporters

Objective: The aim of the present study was to determine whether curcumin (CM) can prevent drug sensitivity of breast cancer (BC) cells when E andβ-E2 are administered together and whether the underlying mechanism involves modulation of drug efflux transporters.Methods: MCF7 BC cells were treated with the vehicle only, E+β-E2, or E+β-E2+CM repeatedly for 8 weeks. Afterward, the cells were harvested,counted, and isolated for total RNA extraction. Total RNA was then processed into cDNA and further processed for the determination of mRNAexpression patterns of drug efflux transporters (P-glycoprotein, BCRP, and MRP1).Results: Decreased sensitivity of BC cells was shown by the increased cell viability of MCF7 cells after 8 weeks. This condition was accompanied withincreased mRNA expression of P-glycoprotein, BCRP, and MRP1 in cells treated with E+β-E2, as compared with the vehicle only. CM, administered incombination with E+β-E2, resulted in decreased cell viability versus E and β-E2 and also decreased in mRNA expression of P-glycoprotein, BCRP, andMRP1.Conclusion: CM partially reversed the sensitivity loss of BC cells to E in the presence of β-E2 by modulating drug efflux transporters.

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