Ieiri Ichiro, Takane Hiroshi, Otsubo Kenji
Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan.
Clin Pharmacokinet. 2004;43(9):553-76. doi: 10.2165/00003088-200443090-00001.
There has been an increasing appreciation of the role of drug transporters in the pharmacokinetic and pharmacodynamic profiles of certain drugs. Among various drug transporters, P-glycoprotein, the MDR1 gene product, is one of the best studied and characterised. P-glycoprotein is expressed in normal human tissues such as liver, kidney, intestine and the endothelial cells of the blood-brain barrier. Apical (or luminal) expression of P-glycoprotein in these tissues results in reduced drug absorption from the gastrointestinal tract, enhanced drug elimination into bile and urine, and impeded entry of certain drugs into the central nervous system. The clinical relevance of P-glycoprotein depends on the localisation in human tissues (i.e. vectorial or directional movement), the therapeutic index of the substrate drug and the inherent inter- and intra-individual variability. With regard to the variability, polymorphisms of the MDR1 gene have recently been reported to be associated with alterations in disposition kinetics and interaction profiles of clinically useful drugs, including digoxin, fexofenadine, ciclosporin and talinolol. In addition, polymorphism may play a role in patients who do not respond to drug treatment. Moreover, P-glycoprotein is an important prognostic factor in malignant diseases, such as tumours of the gastrointestinal tract.A growing number of preclinical and clinical studies have demonstrated that polymorphism of the MDR1 gene may be a factor in the overall outcome of pharmacotherapy for numerous diseases. We believe that further understanding the physiology and biochemistry of P-glycoprotein with respect to its genetic variations will be important to establish individualised pharmacotherapy with various clinically used drugs.
药物转运体在某些药物的药代动力学和药效学特征中所起的作用已越来越受到重视。在各种药物转运体中，P-糖蛋白作为多药耐药基因1（MDR1）的产物，是研究和表征得最为深入的之一。P-糖蛋白在正常人体组织中表达，如肝脏、肾脏、肠道以及血脑屏障的内皮细胞。这些组织中P-糖蛋白的顶端（或管腔）表达导致药物从胃肠道的吸收减少、药物向胆汁和尿液中的排泄增加，以及某些药物进入中枢神经系统受阻。P-糖蛋白的临床相关性取决于其在人体组织中的定位（即矢量或定向运动）、底物药物的治疗指数以及个体间和个体内固有的变异性。关于变异性，最近有报道称MDR1基因多态性与临床常用药物（包括地高辛、非索非那定、环孢素和他林洛尔）的处置动力学和相互作用特征的改变有关。此外，多态性可能在对药物治疗无反应的患者中起作用。而且，P-糖蛋白是恶性疾病（如胃肠道肿瘤）中的一个重要预后因素。越来越多的临床前和临床研究表明，MDR1基因多态性可能是多种疾病药物治疗总体结果的一个影响因素。我们认为，进一步了解P-糖蛋白在其基因变异方面的生理学和生物化学对于建立使用各种临床常用药物的个体化药物治疗至关重要。
