Woodcock B G, Abdel-Rahman M S, Wosch F, Harder S
Department of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt/Main, F.R.G.
Eur J Cancer. 1993;29A(4):559-61. doi: 10.1016/s0959-8049(05)80151-0.
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.
使用平衡透析法和³H标记的长春新碱，在体外研究了长春新碱与α1-酸性糖蛋白（AGP，2mg/ml）溶液的结合情况，以及D,L-维拉帕米、维拉帕米对映体、维拉帕米代谢产物去甲维拉帕米和D617的影响。长春新碱与AGP的结合（52.3±3.6%）在0.002-2.0μg/ml范围内与浓度无关。当加入浓度在5-50μg/ml范围内的D,L-维拉帕米和维拉帕米对映体时，长春新碱从AGP上的置换率在25.1%至81.3%之间变化。相比之下，D617（5-100μg/ml）的置换作用较弱，在0至47%之间变化。在20μg/ml时，D,L-维拉帕米、R-维拉帕米、S-维拉帕米和去甲维拉帕米产生的置换率分别为53.1%、56.8%、58.9%和53.9%，是D617（25%；P = 0.002）的两倍多。得出的结论是，长春新碱、D,L-维拉帕米、维拉帕米异构体和代谢产物在AGP的结合位点相互作用。这些相互作用在多药耐药中可能具有临床重要性，例如在接受维拉帕米和长春花生物碱治疗且AGP水平升高的癌症患者中。
