Advances in P-glycoprotein-based approaches for delivering anticancer drugs: pharmacokinetic perspective and clinical relevance

Abstract

The concomitant use of anticancer P-gp substrate and P-gp inhibitor is an effective and safe way to enhance the bioavailability of anticancer drugs. The poor bioavailability and toxicity of anticancer drugs limit their therapeutic efficacy. These characteristics can be improved by using various nanocarriers which exhibited a high potential to bypass this efflux protein. The best combination of P-gp inhibitor and substrate anticancer drug in a single nanocarrier formulation is a future challenge and is still probably some years away from the marketplace.

Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Multidrug Resistance by a Novel Mechanism Involving the Hijacking of Lysosomal P-Glycoprotein (Pgp)

“…Compared with vehicle-treated control tumors, the efficacy of Dp44mT at reducing tumor growth was Ͼ5-fold more in KBV1 (ϩPgp) relative to KB31 (ϪPgp) xenografts. This result is significant, because attempts to reverse resistance by using MDR modulators have not been successful in clinical trials (4,5). Hence, the ability of Dp44mT to overcome MDR offers a significant advantage over other chemotherapeutics and the unsuccessful attempts to reverse resistance with MDR modulators (4,5).…”

“…resistance to chemotherapeutics by using MDR modulators have not generated useful outcomes in clinical trials (4,5). Hence, there is an increasing need to develop drugs that effectively target drug-resistant tumors.…”

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

“…High ABCB1 levels represent an important cancer cell resistance mechanism [32][33][34]. However, ABCB1 inhibitors failed in a number of clinical cancer trials [32,33].…”

Recent Advances in Chitosan-Based Nanomedicines for Cancer Chemotherapy

“…However, numerous limitations are associated with chemotherapeutic agents that hinder the effectiveness of chemotherapy, e.g., poor aqueous solubility (making them difficult to administer), narrow therapeutic index (which limits the dose and frequency of treatment), non-specific distribution throughout the body (which leads to insufficient penetration into cancer cells) and efflux transporter specificity (which confers cancer cell drug resistance) [1,2]. To overcome these limitations over the past several decades, drug delivery researchers, and formulation scientists have focused their attention toward the development of drug delivery systems that specifically target the site of action and significantly affect the pharmacokinetics and pharmacodynamics of therapeutic agents [3,4].…”