Implication of metabolomics and transporter modulation based strategies to minimize multidrug resistance and enhance site-specific bioavailability: a needful consideration toward modern anticancer drug discovery. (3rd April 2022)

• Record Type: Journal Article
• Authors: Rachmale, Megha; Rajput, Niraj; Jadav, Tarang; Sahu, Amit Kumar; Tekade, Rakesh K.; Sengupta, Pinaki
• Is Part Of: Drug metabolism reviews. Volume 54:Number 2(2022)
• Page Start: 101
• Page End: 119
• Publication Date: 2022-04-03
• Subjects: Drug-metabolizing enzymes and efflux transporters -- PXR receptor -- multi drug resistance -- site-specific bioavailability -- Nanocarrier drug cargo -- anticancer drug development; Drugs -- Metabolism -- Periodicals; Pharmacokinetics -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; 615
• DOI: 10.1080/03602532.2022.2048007
• Languages: English
• ISSNs: 0360-2532

Abstract

Abstract: Induction of drug-metabolizing enzymes and efflux transporters (DMET) through activation of pregnane x receptor (PXR) is the primary factor involved in almost all bioavailability and drug resistance-related problems of anticancer drugs. PXR is a transcriptional regulator of many metabolizing enzymes and efflux transporters proteins like p-glycoprotein (p-gp), multidrug resistant protein 1 and 2 (MRP 1 and 2), and breast cancer resistant protein (BCRP), etc. Several anticancer drugs are potent activators of PXR receptors and can modulate the gene expression of DMET proteins. Involvement of anticancer drugs in transcriptional regulation of DMET can prompt increased metabolism and efflux of their own or other co-administered drugs, which leads to poor site-specific bioavailability and increased drug resistance. In this review, we have discussed several novel strategies to evade drug-induced PXR activation and p-gp efflux including assessment of PXR ligand and p-gp substrate at early stages of drug discovery. Additionally, we have critically discussed the chemical structure and drug delivery-based approaches to avoid PXR binding and inhibit the p-gp activity of the drugs at their target sites.