Verapamil metabolites: potential P-glycoprotein-mediated multidrug resistance reversal agents

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.