Cancer treatment by drugs is seriously limited by P-glycoprotein (P-gp) associated multi-drug resistance (MDR) in various tumor cells. It is now widely recognized that P-gp influences drug transport across various biological membranes. P-gp transporter is widely present in various body tissues affecting absorption, distribution, metabolism and excretion of drugs. Clinical significance of above mentioned carrier is appreciated from the fact that more than fifty percent of existing anti-cancer drugs undergo inhibitable and saturable P-gp mediated efflux. Consequently, there is an increasing trend to optimize pharmacokinetics, enhance antitumour activity and reduce systemic toxicity of existing anticancer drugs by inhibiting P-gp mediated transport. Although a wide variety of P-gp inhibitors have been discovered, research efforts are underway to identify the most appropriate one. Flavanoids belong to the third generation, nonpharmaceutical category of P-gp inhibitors. Among different classes of flavonoids, flavonols are the most explored P-gp inhibitors by several research groups. This could possibly be because of the fact that the effects produced by these are found to be comparable to those of well-known potent P-gp inhibitors verapamil and cyclosporine. Identification of effective P-gp modulator among herbal compounds have an added advantage of being safe, thereby making them ideal candidates for bioavailability enhancement, tissue-penetration (e.g. blood brain barrier), decreasing biliary excretion and multidrug resistance modulating agents. The dual effects, i.e. P-gp modulation and antitumor activity, of these herbal derivatives may synergistically act in cancer chemotherapy. This paper presents an overview of the investigations on the feasibility and application of flavonols as P-gp modulators for improved efficacy of anti-cancer drugs. The review also focuses on flavonol-drug interactions as well as the reversal activity of flavonols useful against MDR.
Keywords: P-glycoprotein, flavonoids, flavonols, multi-drug resistance, chemotherapy, pharmacokinetics
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