Effects of New 4-Aryl-1,4-Dihydropyridines and 4-Arylpyridines on Drug Efflux Mediated by Multidrug Resistance-Associated Protein 1

The purpose of this study is to evaluate the effects of newly synthesized 4-aryl-1,4-dihydropyridine and pyridines on drug efflux mediated by multidrug resistance-associated protein 1 (MRP1, ABCC1). These compounds were designed to maximize inhibition of P-glycoprotein and minimize calcium channel b...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2005-10, Vol.94 (10), p.2256-2265
Main Authors: Zhou, Xiao-fei, Coburn, Robert A., Morris, Marilyn E.
Format: Article
Language:English
Subjects:
ATP-binding cassette (ABC)
Biological and medical sciences
Cell Line, Tumor - drug effects
Cell Survival - drug effects
Daunorubicin - toxicity
dihydropyridines
Dihydropyridines - pharmacology
drug efflux
Drug Interactions
Drug Resistance, Multiple - drug effects
General pharmacology
Glutathione - metabolism
Humans
Inhibitory Concentration 50
Medical sciences
multidrug resistance (MDR)
multidrug resistance-associated protein 1 (MRP1)
Multidrug Resistance-Associated Proteins - antagonists & inhibitors
Multidrug Resistance-Associated Proteins - metabolism
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
pyridines
Pyridines - pharmacology
Time Factors
Vinblastine - metabolism
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Summary:The purpose of this study is to evaluate the effects of newly synthesized 4-aryl-1,4-dihydropyridine and pyridines on drug efflux mediated by multidrug resistance-associated protein 1 (MRP1, ABCC1). These compounds were designed to maximize inhibition of P-glycoprotein and minimize calcium channel binding activity, based on structure modifications of niguldipine. A [3H]vinblastine accumulation study was conducted in human small cell lung cancer H69AR (overexpressing MRP1) and wild type H69 cells. Five out of 16 dihydropyridines and 6 out of 9 pyridines were found to significantly increase the intracellular accumulation of vinblastine in resistant H69AR cells (p
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.20406