Effect of D,L-verapamil, verapamil enantiomers and verapamil metabolites on the binding of vincristine to alpha 1-acid glycoprotein.

Vincristine binding to solutions of alpha 1-acid glycoprotein (AGP, 2 mg/ml) and the effect of D,L-verapamil, verapamil enantiomers and the verapamil metabolites norverapamil and D617 were investigated in vitro using equilibrium dialysis and 3H-labelled vincristine. Vincristine binding to AGP (52.3 +/- 3.6%) was concentration independent over the range 0.002-2.0 micrograms/ml. The displacement of vincristine from AGP varied between 25.1 and 81.3% with D,L-verapamil and verapamil enantiomers added at concentrations in the range 5-50 micrograms/ml. In contrast, the displacement by D617 (5-100 micrograms/ml) was weaker and varied between 0 and 47%. The displacement at 20 micrograms/ml produced by D,L-verapamil, R-verapamil, S-verapamil and norverapamil was 53.1%, 56.8%, 58.9% and 53.9%, respectively, was more than double that for D617 (25%; P = 0.002). It is concluded that vincristine, D,L-verapamil and verapamil isomers and metabolites interact at binding sites on AGP. These interactions may be clinically important in multidrug resistance, for example in cancer patients with elevated levels of AGP undergoing treatment with verapamil and vinca alkaloids.