P-glycoprotein-mediated efflux as a major factor in the variance of absorption and distribution of drugs: modulation of chemotherapy resistance.

Active efflux of many therapeutics and other xenobiotics from cells and tissues by P-glycoprotein (P-gp) can cause dramatic effects on bioavailability. This expulsion of compounds from cells is known as a major form of multiple drug resistance (MDR). Often a significant barrier to oral absorption at the intestine, P-gp also protects the liver, brain, placenta, testes, adrenal gland and other tissues from cytotoxic insult. Due to the wide tolerance of substrate recognition, P-gp can often be the mechanism for significant pharmacokinetic drug interactions when two or more drugs are competing for the P-gp transport site. P-gp levels are also inducible and can be even further elavated in cancer cells, thus contributing to the confounding pleiotropic resistance to chemotherapy and poor treatment prognosis. Consequently, a broad scope of research over 20 years has led to the evaluation of co-therapies intended to augment chemotherapy by inhibiting P-gp. This review includes a list of the currently known P-gp inhibiting adjuvant candidates described in the literature, with associated references and summary data. The summary catalogue of P-gp modulators illustrates the ardent pursuit to overcome this form of therapy resistance and gives examples of clinical success and failure.