Contribution of Uptake and Efflux Transporters to Oral Pharmacokinetics of Furosemide

Background & Objective: Epilepsy is a common and serious chronic neurological disorder that is mainly treated with antiepileptic drugs. Although current antiepileptic drugs used in clinical practice have advanced to the third generation, approximately one-third of patients are refractory to these treatments. More efficacious treatments for refractory epilepsy are therefore needed. A better understanding of the mechanism underlying refractory epilepsy is likely to facilitate the development of a more effective therapy. The abnormal expression and/or dysfunction of efflux transporters, particularly ABC transporters, might contribute to certain cases of refractory epilepsy. Inflammation in the brain has recently been shown to regulate the expression and/or function of ABC transporters in the cerebral vascular endothelial cells and glia of the blood-brain barrier by activating intracellular signalling pathways. Conclusion: Therefore, in this review, we will briefly summarize recent research advances regarding the possible role of neuroinflammation in regulating ABC transporter expression in epilepsy.

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

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2018.v10s1.21 ◽

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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Fructose Induces Fluconazole Resistance in Candida albicans through Activation of Mdr1 and Cdr1 Transporters

International Journal of Molecular Sciences ◽

10.3390/ijms22042127 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2127

Author(s):

Jakub Suchodolski ◽

Anna Krasowska

Keyword(s):

Candida Albicans ◽

Multidrug Resistance ◽

Green Fluorescent Protein ◽

Fluorescent Protein ◽

De Novo ◽

Pathogenic Fungus ◽

Serum Levels ◽

Efflux Transporters ◽

Fluconazole Resistance ◽

Green Fluorescent

Candida albicans is a pathogenic fungus that is increasingly developing multidrug resistance (MDR), including resistance to azole drugs such as fluconazole (FLC). This is partially a result of the increased synthesis of membrane efflux transporters Cdr1p, Cdr2p, and Mdr1p. Although all these proteins can export FLC, only Cdr1p is expressed constitutively. In this study, the effect of elevated fructose, as a carbon source, on the MDR was evaluated. It was shown that fructose, elevated in the serum of diabetics, promotes FLC resistance. Using C. albicans strains with green fluorescent protein (GFP) tagged MDR transporters, it was determined that the FLC-resistance phenotype occurs as a result of Mdr1p activation and via the increased induction of higher Cdr1p levels. It was observed that fructose-grown C. albicans cells displayed a high efflux activity of both transporters as opposed to glucose-grown cells, which synthesize Cdr1p but not Mdr1p. Additionally, it was concluded that elevated fructose serum levels induce the de novo production of Mdr1p after 60 min. In combination with glucose, however, fructose induces Mdr1p production as soon as after 30 min. It is proposed that fructose may be one of the biochemical factors responsible for Mdr1p production in C. albicans cells.

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Non-responder phenotype reveals apparent microbiome-wide antibiotic tolerance in the murine gut

Communications Biology ◽

10.1038/s42003-021-01841-8 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Christian Diener ◽

Anna C. H. Hoge ◽

Sean M. Kearney ◽

Ulrike Kusebauch ◽

Sushmita Patwardhan ◽

...

Keyword(s):

Antibiotic Treatment ◽

Treatment Duration ◽

Efflux Transporters ◽

High Dose ◽

Specific Host ◽

Lactam Antibiotic ◽

Enteric Infections ◽

Community Tolerance ◽

Future Work ◽

Antibiotic Treatment Duration

AbstractBroad spectrum antibiotics cause both transient and lasting damage to the ecology of the gut microbiome. Antibiotic-induced loss of gut bacterial diversity has been linked to susceptibility to enteric infections. Prior work on subtherapeutic antibiotic treatment in humans and non-human animals has suggested that entire gut communities may exhibit tolerance phenotypes. In this study, we validate the existence of these community tolerance phenotypes in the murine gut and explore how antibiotic treatment duration or a diet enriched in antimicrobial phytochemicals might influence the frequency of this phenotype. Almost a third of mice exhibited whole-community tolerance to a high dose of the β-lactam antibiotic cefoperazone, independent of antibiotic treatment duration or dietary phytochemical amendment. We observed few compositional differences between non-responder microbiota during antibiotic treatment and the untreated control microbiota. However, gene expression was vastly different between non-responder microbiota and controls during treatment, with non-responder communities showing an upregulation of antimicrobial tolerance genes, like efflux transporters, and a down-regulation of central metabolism. Future work should focus on what specific host- or microbiome-associated factors are responsible for tipping communities between responder and non-responder phenotypes so that we might learn to harness this phenomenon to protect our microbiota from routine antibiotic treatment.

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Single intravenous and oral pharmacokinetics of danofloxacin in the goat

Small Ruminant Research ◽

10.1016/j.smallrumres.2021.106393 ◽

2021 ◽

Vol 200 ◽

pp. 106393

Author(s):

Irene Sartini ◽

Beata Łebkowska-Wieruszewska ◽

Andrzej Lisowski ◽

Amnart Poapolathep ◽

Victoria Llewelyn ◽

...

Keyword(s):

Oral Pharmacokinetics

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Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications

Pharmaceutics ◽

10.3390/pharmaceutics13060834 ◽

2021 ◽

Vol 13 (6) ◽

pp. 834

Author(s):

Anima M. Schäfer ◽

Henriette E. Meyer zu Schwabedissen ◽

Markus Grube

Keyword(s):

Organic Anion ◽

Physiological Role ◽

Point Of View ◽

Efflux Transporters ◽

Organic Anion Transporting Polypeptides ◽

Current State ◽

P Glycoprotein ◽

The Central Nervous System ◽

And Function ◽

Uptake Transporters

The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples.

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Phosphorylation of MgrA and Its Effect on Expression of the NorA and NorB Efflux Pumps of Staphylococcus aureus

Journal of Bacteriology ◽

10.1128/jb.00018-10 ◽

2010 ◽

Vol 192 (10) ◽

pp. 2525-2534 ◽

Cited By ~ 55

Author(s):

Que Chi Truong-Bolduc ◽

David C. Hooper

Keyword(s):

Staphylococcus Aureus ◽

Multidrug Resistance ◽

Virulence Factors ◽

Double Mutant ◽

Efflux Pumps ◽

Efflux Transporters ◽

Global Regulator ◽

Binding Assays ◽

Genes Encoding ◽

Gel Shift

ABSTRACT MgrA is a global regulator in Staphylococcus aureus that controls the expression of diverse genes encoding virulence factors and multidrug resistance (MDR) efflux transporters. We identified pknB, which encodes the (Ser/Thr) kinase PknB, in the S. aureus genome. PknB was able to autophosphorylate as well as phosphorylate purified MgrA. We demonstrated that rsbU, which encodes a Ser/Thr phosphatase and is involved in the activation of the SigB regulon, was able to dephosphorylate MgrA-P but not PknB-P. Serines 110 and 113 of MgrA were found to be phosphorylated, and Ala substitutions at these positions resulted in reductions in the level of phosphorylation of MgrA. DNA gel shift binding assays using norA and norB promoters showed that MgrA-P was able to bind the norB promoter but not the norA promoter, a pattern which was the reverse of that for unphosphorylated MgrA. The double mutant MgrAS110A-S113A bound to the norA promoter but not the norB promoter. The double mutant led to a 2-fold decrease in norA transcripts and a 2-fold decrease in the MICs of norfloxacin and ciprofloxacin in strain RN6390. Thus, phosphorylation of MgrA results in loss of binding to the norA promoter, but with a gain of the ability to bind the norB promoter. Loss of the ability to phosphorylate MgrA by Ala substitution resulted in increased repression of norA expression and in reductions in susceptibilities to NorA substrates.

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