Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives

Roe, Michael W.; Folkes, Adrian; Ashworth, Philip; Brumwell, Julie; Chima, Lal; Hunjan, Sukhjit; Pretswell, Ian; Dangerfield, Wendy; Ryder, Hamish; Charlton, Peter

doi:10.1016/s0960-894x(99)00030-x

Cited by 153 publications

(113 citation statements)

References 7 publications

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“…Under terms of the Material Transfer Agreement with Xenova Group, Ltd (UK) we could not use their better known P-gp inhibitor tariquidar, previously called XR9576 (Roe et al, 1999) with proprietary compounds in the current collaboration. Instead, we compared the efficacy of tariquidar and DCPQ to enhance brain uptake of [ 11 C]lopramide, which is an avid substrate for P-gp (Sadeque et al, 2000).…”

Section: Effect Of P-gp On Brain Uptake and Peripheral Disposition Ofmentioning

confidence: 99%

The PET Radioligand [11C]MePPEP Binds Reversibly and with High Specific Signal to Cannabinoid CB1 Receptors in Nonhuman Primate Brain

Yasuno

Brown

Zoghbi

et al. 2007

Neuropsychopharmacol

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The cannabinoid CB 1 receptor is one of the most abundant G protein-coupled receptors in the brain and is a promising target of therapeutic drug development. Success of drug development for neuropsychiatric indications is significantly enhanced with the ability to directly measure spatial and temporal binding of compounds to receptors in central compartments. We assessed the utility of a new positron emission tomography (PET) radioligand to image CB 1 receptors in monkey brain. showed that the majority (489%) of brain uptake in regions with high receptor densities was specific and reversibly bound to CB 1 receptors in the high binding regions. [ 11 C]MePPEP was rapidly removed from arterial plasma. Regional brain uptake could be quantified as distribution volume relative to the concentration of parent radiotracer in plasma. The P-glycoprotein (P-gp) inhibitor DCPQ ((R)-4- [(1a,6,10b)-1,1-dichloro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-[(5-quinolinyloxy)methyl]-1-piperazineethanol) did not significantly increase brain uptake of [ 11 C]MePPEP, suggesting it is not a substrate for this efflux transporter at the blood-brain barrier.[ 11 C]MePPEP is a radioligand with high brain uptake, high specific signal to CB 1 receptors, and adequately fast washout from brain that allows quantification with 11 C (half-life ¼ 20 min). These promising results in monkey justify studying this radioligand in human subjects.

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Section: Effect Of P-gp On Brain Uptake and Peripheral Disposition Ofmentioning

confidence: 99%

The PET Radioligand [11C]MePPEP Binds Reversibly and with High Specific Signal to Cannabinoid CB1 Receptors in Nonhuman Primate Brain

Yasuno

Brown

Zoghbi

et al. 2007

Neuropsychopharmacol

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“…5). As a positive control to ensure that 11 C-loperamide is a substrate for P-gp in monkeys, we used tariquidar, which is a potent P-gp inhibitor (25). Tariquidar (8 mg/kg intravenously) was administered 30 min before 11 C-loperamide and increased brain activity about 3-fold.…”

Section: Effect Of Disulfiram On P-gpmentioning

confidence: 99%

“…We gave 2 doses of disulfiram (500 mg) to 3 different monkeys, but it caused insignificant changes in brain uptake of 11 C-loperamide, a known substrate for P-gp. As a control experiment, tariquidar (8 mg/kg intravenously), a potent P-gp inhibitor (25), increased brain uptake of 11 C-loperamide approximately 3-fold (S. Zoghbi, unpublished data, August 2006). Thus, at least at the doses used (cumulative 1,000 mg), disulfiram showed no blockade of P-gp at the monkey blood-brain barrier.…”

Section: Possible Effects Of P-gpmentioning

confidence: 99%

Disulfiram Inhibits Defluorination of 18F-FCWAY, Reduces Bone Radioactivity, and Enhances Visualization of Radioligand Binding to Serotonin 5-HT1A Receptors in Human Brain

Ryu¹,

Liow²,

Zoghbi³

et al. 2007

Journal of Nuclear Medicine

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( 18 F-FCWAY) is a PET radioligand for imaging serotonin 5-hydroxytryptamine-1A receptors in brain. 18 F-FCWAY undergoes significant defluorination, with high uptake of radioactivity in the skull and resulting spillover contamination in the underlying neocortex. The cytochrome P450 enzyme CYP2E1 defluorinates many drugs. We previously showed that miconazole, an inhibitor of CYP2E1, blocks defluorination of FCWAY in rats. Here, we used 18 F-FCWAY to test the ability of the less toxic agent disulfiram to inhibit defluorination in humans. Methods: Eight healthy volunteers underwent a PET scan before and after administration of 500 mg of disulfiram (n 5 6) or 2,000 mg of cimetidine (n 5 2). Seven of the subjects had arterial blood sampling during both scans. Results: Although cimetidine had relatively small and variable effects on 2 subjects, disulfiram reduced skull radioactivity by about 70% and increased peak brain uptake by about 50% (n 5 5). Disulfiram decreased plasma-free 18 F-fluoride ion (from peak levels of 340% 6 62% standardized uptake value (SUV) to 62% 6 43% SUV; P , 0.01) and increased the concentration of the parent 18 F-FCWAY (with a corresponding decrease of clearance from 14.8 6 7.8 LÁh 21 at baseline to 7.9 6 2.8 LÁh 21 after drug treatment (P , 0.05). Using compartmental modeling with input of both 18 F-FCWAY and the radiometabolite 18 F-FC (trans-4-fluorocyclohexanecarboxylic acid), distribution volumes attributed to the parent radioligand unexpectedly decreased about 40%-60% after disulfiram, but the accuracy of the radiometabolite correction is uncertain. Disulfiram changed the shape of the brain time-activity curves in a manner that could occur with inhibition of the efflux transporter P-glycoprotein (P-gp). However, disulfiram showed no in vivo efficacy in monkeys to enhance the uptake of the known P-gp substrate 11 C-loperamide, suggesting that the effects of disulfiram in humans were mediated entirely by inhibition of CYP2E1. Conclusion: A single oral dose of disulfiram inhibited about 70% of the defluorination of 18 F-FCWAY, increased the plasma concentration of 18 F-FCWAY, increased brain uptake of activity, and resulted in better visualization of 5-HT 1A receptor in the brain. Disulfiram is a safe and well-tolerated drug that may be useful for other radioligands that undergo defluorination via CYP2E1.

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“…The third generation MDR modulators have been designed because of the need for compounds lacking other pharmacological effects, which thereby confer greater selectivity and specificity for Pglycoprotein. These modulators include LY335979 [168], R101933 [184] and XR9576 (Tariquidar) [184], which are the more potent and specific P-glycoprotein modulators. Drug binding experiments and kinetic analysis have shown that XR9576 inhibits P-glycoprotein function by binding at a modulatory site, which is distinct from the site of interaction of Pglycoprotein substrates [185].…”

Section: Specific Inhibitorsmentioning

confidence: 99%

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Safa

2004

CMCACA

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A major problem in cancer treatment is the development of resistance to multiple chemotherapeutic agents in tumor cells. A major mechanism of this multidrug resistance (MDR) is overexpression of the MDR1 product P-glycoprotein, known to bind to and transport a wide variety of agents. This review concentrates on the progress made toward understanding the role of this protein in MDR, identifying and characterizing the drug binding sites of P-glycoprotein, and modulating MDR by P-glycoprotein-specific inhibitors. Since our initial discovery that Pglycoprotein binds to vinblastine photoaffinity analogs, many P-glycoprotein-specific photoaffinity analogs have been developed and used to identify the particular domains of Pglycoprotein capable of interacting with these analogs and other P-glycoprotein substrates. Furthermore, significant advances have been made in delineating the drug binding sites of this protein by studying mutant P-glycoprotein. Photoaffinity labeling experiments and the use of sitedirected antibodies to several domains of this protein have allowed the localization of the general binding domains of some of the cytotoxic agents and MDR modulators on P-glycoprotein. Moreover, site-directed mutagenesis studies have identified the amino acids critical for the binding of some of these agents to P-glycoprotein. Furthermore, equilibrium binding assays using plasma membranes from MDR cells and radioactive drugs have aided our understanding of the modes of drug interactions with P-glycoprotein. Based on the available data, a topological model of Pglycoprotein and the approximate locations of its drug binding sites, as well as a proposed classification of multiple drug binding sites of this protein, is presented in this review.

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Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives

Cited by 153 publications

References 7 publications

The PET Radioligand [11C]MePPEP Binds Reversibly and with High Specific Signal to Cannabinoid CB1 Receptors in Nonhuman Primate Brain

The PET Radioligand [11C]MePPEP Binds Reversibly and with High Specific Signal to Cannabinoid CB1 Receptors in Nonhuman Primate Brain

Disulfiram Inhibits Defluorination of 18F-FCWAY, Reduces Bone Radioactivity, and Enhances Visualization of Radioligand Binding to Serotonin 5-HT1A Receptors in Human Brain

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

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