Role of SLC xenobiotic transporters and their regulatory mechanisms PDZ proteins in drug delivery and disposition.

Various types of xenobiotic (or drug) transporters have been recently identified to play important roles as barriers against toxic compounds and influx pumps to take up nutrients into the body. Since those xenobiotic transporters generally have wide range of recognition specificity and accept various types of compounds as substrates, localization and functional expression of such transporters could be one of the critical factors that affect the disposition and subsequent biological activity of therapeutic agents. Identification and characterization of drug transporters have given us a scientific basis for understanding drug delivery and disposition, as well as the molecular mechanisms of drug interaction and inter-individual/inter-species differences. To precisely understand pharmacological roles of the transporters in the body, it is also important to clarify molecular mechanisms involved in regulation of the transporters. As a first step to clarify the regulatory mechanisms that govern cell-surface expression and/or function of these transporters, recent researches have focused on PDZ (PSD-95/Discs-large/ZO-1) binding motif localized on carboxylic terminus of several types of xenobiotic transporters. Most of the transporters showing direct interaction potential with the PDZ domain-containing proteins are expressed on apical membranes in epithelial cells of kidney and/or small intestine, implying that such protein-protein interaction may play a role in apical localization of the transporters. In this mini-review article, we summarize importance of transporters and their regulatory mechanisms in drug delivery and disposition, focusing on several aspects of transporter-mediated drug targeting.