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.
Johnson
W W
WW
Schering-Plough Research Institute, Lafayette, New Jersey, USA. william.w.johnson@spcorp.com
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000042:Absorption / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000277:Adjuvants, Pharmaceutic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D017024:Chemotherapy, Adjuvant / Q000379:methods*; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D006801:Humans; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000277:Adjuvants, Pharmaceutic; D000970:Antineoplastic Agents