P-glycoprotein (P-gp/MDR1)/ABCB1

The ABCB1 gene was cloned from non-polarized tumor cells where it confers multidrug resistance. P-gp is also expressed on organ barriers where it plays a protective role and affects the ADME of drugs. P-gp causes clinically significant DDIs, particularly for those drugs with a narrow therapeutic index. Regulatory agencies require the potential DDI risk to be evaluated in drug development. P-gp limits the entry of substrate drugs into the brain; therefore, drug selection during the discovery process must involve rational design to engineer out interactions with P-gp for centrally acting drugs or, instead, to integrate P-gp interactions as beneficial factors for reduced CNS side effects. Considerable species differences in P-gp expression and function exist. While the Mdr gene is duplicated by Mdr1a and Mdr1b in preclinical species, the single MDR1-encoded P-gp in humans fulfills the functions of the two P-gp isoforms. P-gp function and expression are associated with physiological and pathophysiological conditions such as the pathogenesis of Alzheimer’s disease. It could become a new therapeutic target for treatment of Alzheimer’s disease. Developing a P-gp modulator for chemotherapy through restoring sensitivity to anticancer reagents has emerged as a new focus in the pharmaceutical industry. However, clinical studies for P-gp modulators are not encouraging because the toxicity profiles of anticancer drugs have not been improved.