MDR Expression in Normal Tissues: Pharmocologic Implication for the Clinical Use of P-Glycoprotein Inhibitors

Lum, Bert L.; Gosland, Michael P.

doi:10.1016/s0889-8588(18)30097-2

Cited by 120 publications

(69 citation statements)

References 39 publications

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“…In this study, we address the question as to whether MDR1, which is widely expressed in normal tissues (13), is involved in GSL synthesis in cultured cells in general. These studies fill a major gap in understanding the mechanism of GSL biosynthesis and demonstrate a new, unsuspected distinction between acidic and neutral GSL synthesis.…”

Section: Glccermentioning

confidence: 99%

Role of Multiple Drug Resistance Protein 1 in Neutral but Not Acidic Glycosphingolipid Biosynthesis

Rosa

Sillence

Ackerley

et al. 2004

Journal of Biological Chemistry

109

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MDR1a, 1b, MRP1) mouse fibroblasts showed the same loss of neutral glycosphingolipid (glucosyl ceramide, lactosyl ceramide) but not ganglioside (GM3) synthesis, confirming the proposed role for MDR1 translocase activity. Cryo-immunoelectron microscopy showed MDR1 was predominantly intracellular, largely in rab6-containing Golgi vesicles and Golgi cisternae, the site of glycosphingolipid synthesis. These studies identify MDR1 as the major glucosyl ceramide flippase required for neutral glycosphingolipid anabolism and demonstrate a previously unappreciated dichotomy between neutral and acid glycosphingolipid synthesis.

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Section: Glccermentioning

confidence: 99%

Role of Multiple Drug Resistance Protein 1 in Neutral but Not Acidic Glycosphingolipid Biosynthesis

Rosa

Sillence

Ackerley

et al. 2004

Journal of Biological Chemistry

109

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“…The P-glycoprotein (Pgp) transporter is an ATP-powered efflux pump that plays a major role in cardiovascular DDIs and effluxes a diverse range of cardiovascular therapeutics [6,7]. The transporter is expressed in the brain, intestines, liver, placenta and the kidneys [8,9] Abbreviations: COPASI, complex pathway simulator; DDI, drug-drug interaction; DDM, n-dodecyl-β-D-maltoside; EGTA, ethylene glycol tetraacetic acid; L, ligand; NATA, N-acetyl-L-tryptophanamide; NBD, nucleotide-binding domain; Ni-NTA, nickel-nitrilotriacetic acid; Pgp, P-glycoprotein; STD, saturation transfer difference; STDD, saturation transfer double difference. 1 To whom the correspondence should be addressed (email audie@uga.edu).…”

Section: Introductionmentioning

confidence: 99%

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

2016

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SynopsisDrug-drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug-Pgp interactions, verapamil was found to have little effect on digoxin-Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin-Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil-digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes.

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“…The non-immunosuppressive analog of CsA, PSC 833, has demonstrated superior MDR reversal efficacy in conjunction with daunorubicin, DOX, vincristine, vinblastine, taxol, or mitoxantrone in many cell lines in vitro at concentrations of 0.5-2 mM [143]. Although these agents circumvented many of the problems experienced with first generation MDR modulators, when these agents were co-administered with anticancer agents for modulating P-gp-based MDR, they influenced the pharmacokinetics and biodistribution properties of the anticancer drugs, which resulted in increased toxicity to normal organs such as liver and kidney [144].…”

Section: Second Generation Modulatorsmentioning

confidence: 99%

Multidrug Resistence and Breast Cancer

Zhou¹,

Zhang²

2012

Targeting New Pathways and Cell Death in Breast Cancer

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MDR Expression in Normal Tissues: Pharmocologic Implication for the Clinical Use of P-Glycoprotein Inhibitors

Cited by 120 publications

References 39 publications

Role of Multiple Drug Resistance Protein 1 in Neutral but Not Acidic Glycosphingolipid Biosynthesis

Role of Multiple Drug Resistance Protein 1 in Neutral but Not Acidic Glycosphingolipid Biosynthesis

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

Multidrug Resistence and Breast Cancer

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