Department of Pharmaceutical Sciences, Wilkes University, Wilkes-Barre, PA 18766, USA.
Biopharm Drug Dispos. 2010 Jan;31(1):1-71. doi: 10.1002/bdd.693.
Our understanding of the mechanisms behind inter- and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with organic anion transporters (OATs). Collectively, these transporters are nearly ubiquitously expressed in barrier epithelia. Moreover, several reports indicate that OATs are subject to diverse forms of regulation, much like drug metabolizing enzymes and receptors. Thus, critical to furthering our understanding of patient- and condition-specific responses to pharmacotherapy is the complete characterization of OAT interactions with drugs and regulatory factors. This review provides the reader with a comprehensive account of the function and substrate profile of cloned OATs. In addition, a major focus of this review is on the regulation of OATs including the impact of transcriptional and epigenetic factors, phosphorylation, hormones and gender.
我们对药物反应中个体间和个体内变异性背后的机制的理解还不够充分。细胞色素 P450 药物代谢酶领域的进展引人注目，但药物转运体领域的进展却落后了。然而，目前人们对药物载体介导的药物处置的兴趣正在大幅上升。这一点在 2006 年 FDA 向制药行业发布的指导意见中得到了体现。该指导意见建议业界确定新型药物实体是否与转运体相互作用。这一建议可能源于这样一种观察，即几种新型克隆转运体对各种已批准药物的处置有重大影响。许多药物具有阴离子官能团，因此与有机阴离子转运体（OAT）相互作用。这些转运体共同在屏障上皮细胞中几乎普遍表达。此外，有几项报告表明，OATs 受到多种形式的调节，就像药物代谢酶和受体一样。因此，要深入了解患者和特定条件下对药物治疗的反应，关键是要全面描述 OAT 与药物和调节因子的相互作用。这篇综述为读者提供了关于克隆 OAT 的功能和底物特征的全面描述。此外，本综述的重点主要是 OAT 的调节，包括转录和表观遗传因素、磷酸化、激素和性别对 OAT 的影响。
