Woodland Cindy, Koren Gideon, Wainer Irving W, Batist Gerry, Ito Shinya
Division of Clinical Pharmacology and Toxicology, The Research Insititute, The Hospital for Sick Children, Department of Pharmacology, The University of Toronto, Toronto, ON M5G 1X8, Canada.
Can J Physiol Pharmacol. 2003 Aug;81(8):800-5. doi: 10.1139/y03-073.
Multidrug resistance in cancer chemotherapy frequently correlates with overexpression of the P-glycoprotein drug transporter. Attempts to reverse P-glycoprotein-mediated multidrug resistance with racemic verapamil or its less toxic (R)-enantiomer have been complicated by cardiotoxicity. The objective of this study was to investigate the effects of the major verapamil metabolite, norverapamil, as well as the PR-22 and D-620 metabolites, on P-glycoprotein-mediated drug transport. We measured the basolateral-to-apical fluxes of the P-glycoprotein substrates digoxin and vinblastine in the presence and absence of verapamil, (R)-norverapamil, (S)-norverapamil, racemic norverapamil, PR-22, or D-620 across confluent monolayers of Madin-Darby canine kidney (MDCK) cells that express P-glycoprotein on their apical membranes. Verapamil and norverapamil nonstereospecifically inhibited the renal tubular secretion of digoxin and vinblastine similarly in a dose-dependent manner. However, there was no decrease in the cellular accumulation of digoxin and vinblastine, suggesting that neither verapamil nor norverapamil prevent the substrates from entering the MDCK cells. Furthermore, the norverapamil metabolite P-22 also inhibited the secretion of these P-glycoprotein substrates. Our results suggest that the verapamil metabolites norverapamil and PR-22, which are less cardiotoxic than the parent compound, have comparable inhibitory abilities to verapamil (norverapamil greater than PR-22) and may be useful in reversing resistance to P-glycoprotein substrates.
癌症化疗中的多药耐药性常常与P-糖蛋白药物转运体的过表达相关。试图用消旋维拉帕米或其毒性较小的（R）-对映体来逆转P-糖蛋白介导的多药耐药性，却因心脏毒性而变得复杂。本研究的目的是调查维拉帕米的主要代谢产物去甲维拉帕米以及PR-22和D-620代谢产物对P-糖蛋白介导的药物转运的影响。我们在存在和不存在维拉帕米、（R）-去甲维拉帕米、（S）-去甲维拉帕米、消旋去甲维拉帕米、PR-22或D-620的情况下，测量了P-糖蛋白底物地高辛和长春碱在表达P-糖蛋白的顶膜的汇合的Madin-Darby犬肾（MDCK）细胞单层上从基底外侧到顶端的通量。维拉帕米和去甲维拉帕米以剂量依赖性方式非立体特异性地类似地抑制地高辛和长春碱的肾小管分泌。然而，地高辛和长春碱的细胞内积累没有减少，这表明维拉帕米和去甲维拉帕米都不能阻止底物进入MDCK细胞。此外，去甲维拉帕米代谢产物P-22也抑制这些P-糖蛋白底物的分泌。我们的结果表明，比母体化合物心脏毒性更小的维拉帕米代谢产物去甲维拉帕米和PR-22具有与维拉帕米相当的抑制能力（去甲维拉帕米大于PR-22），并且可能有助于逆转对P-糖蛋白底物的耐药性。
