Overlapping Ligand Specificity of P-Glycoprotein and Serum α1-Acid Glycoprotein:Evidences and Potential Implications
Plasma α1-acid glycoprotein (AGP) is an important modulator of drug disposition, since it binds and transports of a vast array of pharmaceutical agents. The ABC transporter efflux pump, P-glycoprotein (P-gp), also recognizes and binds a broad range of weakly basic and uncharged xenobiotics. Its efflux activity plays a key role in pharmacokinetics of drugs, and overexpression of P-gp in malignant cells confers multidrug resistance (MDR) to anticancer agents. Comparison of ligand specificities of AGP and P-gp revealed high similarity showing that both proteins interact with the same therapeutic classes of drugs (α/β-blockers, anticancer agents, Ca2+ antagonists, antipsychotics/neuroleptics, HIV protease inhibitors etc.) as well as with additional endo- and exogenous compounds (steroids, dyes, natural substances). A wealth of examples are presented to show the potential use of drug-AGP binding data to predict drug-P-gp interactions and vice versa. In addition, structural and functional similarities between AGP and P-gp have been highlighted. Based on these data, several proposals have been made: 1) AGP and P-gp might act synergistically in protecting cells from harmful xenobiotics; 2) An extensive shared list of their ligands allows prediction of mutual binding interactions; 3) Interaction of drugs and drug candidates, both with AGP and P-gp, should be considered to optimize pharmacotherapy and to delineate the causes of drug-drug interactions; 4) Structures of known AGP binders could be exploited in searching for novel scaffolds of P-gp modulators to overcome cancer MDR and efflux-mediated resistance in microorganisms and parasites; 5) Novel fluorescent probes for studying P-gp structure and function can be pre-selected among AGP binder agents.
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Document Type: Research Article
Publication date: August 1, 2007
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- Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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