Relling M V
Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Ther Drug Monit. 1996 Aug;18(4):350-6. doi: 10.1097/00007691-199608000-00006.
Agents (modulators) that reverse the in vitro resistance of tumor cells to anticancer drugs that are substrates for P-glycoprotein (Pgp, the product of the MDR1 gene) have been given to patients concurrently with anticancer drugs in an attempt to improve therapeutic response. The vast majority of investigations into these drugs indicate that Pgp modulators decrease the systemic clearance of anticancer drugs, thus potentially nonselectively increasing exposure to normal and malignant cells and thereby potentially increasing the severity and/or incidence of adverse effects associated with the anticancer therapy. Mechanisms by which Pgp modulators could alter the pharmacokinetics of the anticancer agent include competition for cytochrome P450 intestinal or liver metabolism, inhibition of Pgp-mediated biliary excretion or intestinal transport, or inhibition of renal elimination. It is suggested that administration of Pgp modulators is unlikely to improve the therapeutic index for anticancer drugs unless agents that lack significant pharmacokinetic interactions are found. Moreover, it will likely be required that there be some cancer-tissue selectivity for modulators in order to avoid collaterally increasing the sensitivity of normal Pgp-expressing tissues to the anticancer drug.
能逆转肿瘤细胞对作为P-糖蛋白（Pgp，MDR1基因产物）底物的抗癌药物的体外耐药性的药物（调节剂）已与抗癌药物同时给予患者，以试图改善治疗反应。对这些药物的绝大多数研究表明，Pgp调节剂会降低抗癌药物的全身清除率，从而可能非选择性地增加正常细胞和恶性细胞的暴露量，进而可能增加与抗癌治疗相关的不良反应的严重程度和/或发生率。Pgp调节剂改变抗癌药物药代动力学的机制包括竞争细胞色素P450肠道或肝脏代谢、抑制Pgp介导的胆汁排泄或肠道转运，或抑制肾脏排泄。有人提出，除非找到缺乏显著药代动力学相互作用的药物，否则给予Pgp调节剂不太可能提高抗癌药物的治疗指数。此外，为了避免附带增加正常表达Pgp的组织对抗癌药物的敏感性，调节剂可能需要具有一定的癌组织选择性。
