Research of transporter-adaptor network as target of drug effect and toxicity

转运蛋白是参与药物分子通过质膜渗透的膜蛋白。虽然它们被认为在药物吸收和处置中起着基本作用，但关于它们与药物功效和毒性的直接关系的信息很少。因此，本研究的目的是通过关注转运蛋白的衔接蛋白来阐明转运蛋白的药代动力学、药效学和毒理学作用，这在我们之前的研究中已经得到了阐明。作为这项资助的最终结果，我们已经澄清了(i)肉碱/有机阳离子转运体（OCTNs）在小肠、肝脏、肾脏和心脏的药物处置和疗效中的作用，（ii）内流转运体和外排转运体在胃肠道药物吸收中的作用，以及（iii）三种肠道内流转运体通过适配器蛋白PDZK1直接相互作用和调节。

Transporters are the membrane proteins involved in permeation of drug molecules across plasma membranes. Although they are assumed to play fundamental roles in drug absorption and disposition, little information is available on their direct association with drug efficacy and toxicity. Therefore, the aim of the present study was to clarify pharmacokinetic, pharmacodynamic and toxicodynamic roles of transporters by focusing on their adaptor proteins which have already been clarified by our previous studies. As the final results of this grant, we have clarified (i) the roles of carnitine/organic cation transporters (OCTNs) in drug disposition and efficacy in small intestine, liver, kidney and heart, (ii) the roles of influx and efflux transporters in gastrointestinal drug absorption, and (iii) direct interaction and regulation of three intestinal influx transporters by an adaptor protein PDZK1.