Walle T, Kumar G N, McMillan J M, Thornburg K R, Walle U K
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston 29425.
Biochem Pharmacol. 1993 Nov 2;46(9):1661-4. doi: 10.1016/0006-2952(93)90336-u.
Metabolism of the anticancer drug taxol was investigated in freshly isolated rat hepatocytes. Two main metabolites were separated by reversed-phase HPLC and shown by tandem mass spectrometry to be monohydroxylated metabolites. Kinetic studies revealed apparent Km values of 68 and 61 microM with identical Vmax values for the two metabolites. Verapamil and midazolam, but not phenacetin, showed concentration-dependent inhibition of taxol metabolism with both metabolites being affected equally. The IC50 was about 100 microM for verapamil and 25 microM for midazolam. These observations demonstrate for the first time in vitro metabolism of taxol and suggest that the metabolism may be subject to potentially important interactions with numerous other drugs.
在新鲜分离的大鼠肝细胞中研究了抗癌药物紫杉醇的代谢情况。通过反相高效液相色谱法分离出两种主要代谢产物，串联质谱分析表明它们是单羟基化代谢产物。动力学研究显示，这两种代谢产物的表观 Km 值分别为 68 和 61 μM，Vmax 值相同。维拉帕米和咪达唑仑（而非非那西丁）对紫杉醇代谢表现出浓度依赖性抑制，两种代谢产物受到的影响相同。维拉帕米的 IC50 约为 100 μM，咪达唑仑的 IC50 为 25 μM。这些观察结果首次证明了紫杉醇的体外代谢，并表明该代谢可能与许多其他药物存在潜在的重要相互作用。
