Abstract

Drug transporters are modulators for drug absorption, distribution, and excretion. Key drug transporters including P-glycoprotein and breast cancer resistance protein of the ABC superfamily; organic anion transporting polypeptide 1B1 and 1B3, organic anion transporter 1 and 3, and organic cation transporter 2, as well as multidrug and toxin extrusion 1 and 2 of the SLC superfamily have been recommended by regulatory agencies to be investigated and evaluated in drug-drug interaction (DDI) studies due to their important roles in determining the efficacy, toxicity and DDI of various drugs. Drug transporters are subjected to multiple levels of control and post-translational modifications (PTMs) provide rapid and versatile ways of regulation. Under pathological and/or pharmacological conditions, PTMs may be altered in the cellular system, leading to functional changes of transporter proteins. Phosphorylation is by far the most actively investigated form of PTMs in the regulation of transporters. Further, studies in recent years also found that protein kinases coordinate with other PTMs for the dynamic control of these membrane proteins. Here we summarized the regulation of major drug transporters by protein kinases and their cross-talking with other PTMs that may generate a complex regulatory network for fine-tuning the function of these important drug processing modulators.

Significance Statement

Kinases regulate drug transporters in versatile manners;

Kinase regulation cross-talks with other PTMs, forming a complex network for transporter regulation;

Pathological and/or pharmacological conditions may alter PTMs and affect transporter function with different molecular mechanisms.