The physiological role of drug transporters

Abstract

Transporters comprise the largest family of membrane proteins in human organism, including members of solute carrier transporter and ATP-binding cassette transporter families. They play pivotal roles in the absorption, distribution and excretion of xenobiotic and endogenous molecules. Transporters are widely expressed in various human tissues and are routinely evaluated during the process of drug development and approval. Over the past decade, increasing evidence shows that drug transporters are important in both normal physiology and disease. Currently, transporters are utilized as therapeutic targets to treat numerous diseases such as diabetes, major depression, hypertension and constipation. Despite the steady growth of the field of transporter biology, more than half of the members in transporter superfamily have little information available about their endogenous substrate(s) or physiological functions. This review outlines current research methods in transporter studies, and summarizes the drug-transporter interactions including drug-drug and drug-endogenous substrate interactions. In the end, we also discuss the therapeutic perspective of transporters based on their physiological and pathophysiological roles.

Figure 1

Cartoon illustration of the physiological roles and therapeutic implications of OCT1, SLC13A5 and ZnT8 in glucose metabolism, lipogenesis and insulin pathway. Inhibition of OCT1 (e.g., metformin treatment) results in lowered hepatic thiamine uptake, and consequently reduced TPP levels. The reduced ATP production, due to the decreased PDH and OGDH activity, triggers AMPK activation. The inhibition of SLC13A5 leads to lowered cytosol citrate contents, which attenuate the activating effect of citrate in malonyl-CoA synthesis. Both OCT1 and SLC13A5 inhibition reduce TG synthesis in the liver. Inhibition of ZnT8 causes reduced zinc release from the β-cell, and thus attenuates the autocrine effect of zinc in glucose induced insulin production; the hepatic zinc content is also reduced, with concomitant increased insulin clearance. The effects of OCT1, SLC13A5 and ZnT8 inhibition are shown with red, yellow and blue arrows respectively