P-glycoprotein Inhibitors

P-glycoprotein Inhibitors

P-glycoprotein (P-gp) is an active efflux transporter that is carrier-mediated transport system, present in many tissues which are determined by gene MDR1 (Multi-drug resistance). The function of P-gp is to reduce toxic/foreign substances (including drugs) by forcing them back into the lumen from the cells. P-gp substrates are categorized as inhibitors (e.g. verapamil) and inducers (e.g. rifampicin). P-gp inhibitors increase bioavailability of drugs while there is decrease in bioavailability using P-gp inducers, which leads to resistance from various drugs because of efflux pump.

P-gp inhibitors are categorized into various classes based upon their development recently third-generation p-gp inhibitors are designed by QSAR (Quantitative-structure activity relationship), HTS (High throughput screening) and combinatorial screening providing 10 times increase in potency.

Plant-based inhibitors like ginseng, kendarimide (Peptide) are safe and non-toxic. Certain formulations like liposomes, polymer conjugates they are transported by endocytosis hence they bypass p-gp pump. Upcoming p-gp inhibitors are peptide inhibitors like reversin 11 which bind to allosteric site of p-gp thus modulating its structure. P-gp expression suppressers like copper N-(2-hydroxy acetophenone) glycinate (CuNG).

Mechanism of p-gp inhibitors involves inhibition of drug binding site by either competitive, non-competitive or by allosteric site, by interfering with ATP hydrolysis or changing the integrity of lipids of cell membrane.

There are many pharmacotherapeutic agents used clinically that can be co-administered with P-gp inhibitors for providing effective treatment like dronedarone which enhances the bioavailability of dabigatran by 99%.

Evolution of newer P-gp inhibitors can be done by molecular modeling, screening with in-silico and in-vitro studies, characterization by in-situ and in-vivo studies followed by clinical trials to access toxicity and drug interaction.

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