Nonstereoselective norverapamil inhibition of renal tubular digoxin and vinblastine secretion

The use of racemic veraparnil to reverse multidrug resistance is limited by its cardiac toxicity; hence, the use of the less cardiotoxic enantiomer, R-verapamil, is preferable. We investigated the effects of the enantiomers of the major metabolite, norverapamil (NORVER), on P-glycoprotein-mediated drug transport of digoxin (DIG) and vinblastine (VBL) across confluent monolayers of renal tubular cells. The basolateral-to-apical fluxes of radiolabelled DIG and VBL across MDCK renal tubular cells grown on the permeable membranes of tissue culture inserts were examined in the absence and presence of R-, S-, and R,S-NORVER. The enantiomeric and racemic mixtures of NORVER (10μM) significantly inhibited the net renal tubular secretion of DIG and VBL across MDCK cells suggesting that NORVER inhibits P-glycoprotein. While this interaction is dose-dependent, there is no statistically significant difference in inhibition between the two enantiomers. NORVER appears to have similar inhibitory potency to verapamil and therefore may be useful in the prevention of multidrug resistance to cancer chemotherapy.