Silverman J A
AvMax, Inc., South San Francisco, CA 94080, USA.
Pharm Biotechnol. 1999;12:353-86. doi: 10.1007/0-306-46812-3_13.
P-glycoprotein was initially isolated due to its role in multidrug resistance to cancer chemotherapeutics. Recent work, however, makes it increasingly apparent that this transporter is also involved in the pharmacokinetics of many drugs. P-gp is strategically expressed in the luminal epithelial cells of organs often associated with drug absorption and disposition, for example, hepatocyte canalicular membrane, renal proximal tubules, and the intestinal mucosa. P-gp is also expressed in the endothelial cells comprising the blood-brain barrier. This localization clearly suggests the potential for this protein to serve as a protective mechanism against entry of toxic xenobiotics and also suggests that P-gp is well situated to participate in the removal of therapeutic agents. Numerous investigations with drugs such as digoxin, etoposide, cyclosporine, vinblastine, Taxol, loperamide, dom-peridone, and ondansteron demonstrate that P-gp has an important role in determining the pharmacokinetics of substrate drugs. Pharmacological modulation of P-gp function to increase drug bioavailability, both on a organismal and a cellular level, is one approach currently being explored to enhance therapeutic effectiveness. This approach is not without potential collateral consequences given the wide tissue distribution of P-gp. While animals deficient in P-gp are viable and without obvious abnormalities, the pharmacokinetics and toxic consequences of several compounds are significantly altered in these animals. Thus blockade of the protective P-gp barrier in humans may have adverse effects on substrate drugs. In particular, this situation may arise when several compounds which may be substrates compete for P-gp-mediated transport. Additional multidrug transporters, notably MRP and family members, have been identified and may also determine the fate of pharmaceuticals. Further understanding the physiological role of each of the multidrug transporters is critical for determining their role in pharmacokinetics and for evaluating the consequences of modification of their activities. Such information is also important in the development of novel drugs which may be substrates for these transporters.
P-糖蛋白最初因其在癌症化疗多药耐药性中的作用而被分离出来。然而，最近的研究越来越明显地表明，这种转运蛋白也参与了许多药物的药代动力学过程。P-糖蛋白在通常与药物吸收和处置相关的器官腔上皮细胞中战略性地表达，例如肝细胞膜小管、肾近端小管和肠黏膜。P-糖蛋白也表达于构成血脑屏障的内皮细胞中。这种定位清楚地表明该蛋白有可能作为一种保护机制，防止有毒异生素的进入，也表明P-糖蛋白处于参与清除治疗药物的有利位置。对诸如地高辛、依托泊苷、环孢素、长春碱、紫杉醇、洛哌丁胺、多潘立酮和昂丹司琼等药物的大量研究表明，P-糖蛋白在决定底物药物的药代动力学方面具有重要作用。在机体和细胞水平上对P-糖蛋白功能进行药理学调节以提高药物生物利用度，是目前正在探索的一种提高治疗效果的方法。鉴于P-糖蛋白广泛的组织分布，这种方法并非没有潜在的附带后果。虽然缺乏P-糖蛋白的动物能够存活且无明显异常，但几种化合物在这些动物中的药代动力学和毒性后果会发生显著改变。因此，阻断人体中保护性的P-糖蛋白屏障可能会对底物药物产生不利影响。特别是，当几种可能作为底物的化合物竞争P-糖蛋白介导的转运时，就可能出现这种情况。已经鉴定出其他多药转运蛋白，尤其是多药耐药相关蛋白（MRP）及其家族成员，它们也可能决定药物的命运。进一步了解每种多药转运蛋白的生理作用对于确定它们在药代动力学中的作用以及评估其活性改变的后果至关重要。这些信息在开发可能是这些转运蛋白底物的新型药物方面也很重要。
