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学科主题物理化学
Metabolism of 7-epi-paclitaxel by Human Cytochrome P450 Enzymes: Effect of Epimer-epimer Interaction on the Metabolic Elimination of Paclitaxel
Zhang YY(张延延); Zhang JW(张江伟); Ge GB(葛广波); Liu Y(刘勇); Yang L(杨凌)
会议名称2nd ASIAN PACIFIC REGIONAL ISSX MEETING
会议日期2008-5-11
2008-05-11
会议地点中国
页码26/2
ISSN0360-2532
部门归属十八室
主办者DRUG METABOLISM REVIEWS
英文摘要-epi-paclitaxel is the principal degradant of paclitaxel under physiological conditions. Human liver microsomal incubation of 7-epi-paclitaxel in the presence of NADPH resulted in the formation of two monohydroxylated metabolites (M-1 and M-2), which were detected by LC/MS. The metabolic sites occurred at the C13 side chain for M-1 and taxane core ring for M-2, respectively. Chemical inhibition studies, correlation studies, and assays with individual cDNA-expressed P450s indicated that formation of M-1 was mediated by CYP3A4 and M-2 was mediated by CYP2C8. The initial rates of formation of paclitaxel metabolites were about 4-fold higher than those of 7-epi-paclitaxel as CYP2C8 being the major metabolic enzyme. Both CYP3A4 and CYP2C8-catalyzed hydroxylation resulted in minor differences of Clint between these epimers; however, the affinity of CYP2C8 was 13-fold higher for 7-epi-paclitaxel than for paclitaxel (Km 1.59 versus 20.32 µM) that indicated stereoselectivity in metabolism. 7-epi-paclitaxel had only a modest effect on the 3''p-hydroxylation of paclitaxel, whereas efficiently suppressed the formation of 6α-hydroxypaclitaxel in a concentration-dependent manner (IC50≈3.03 μM, Ki≈1.8 μM). The present study demonstrated that the possible epimer-epimer interaction might attribute to the saturation of paclitaxel metabolism by CYP2C8. This information could help to understand the disproportional increase of paclitaxel in systemic exposure with dose escalation. To our knowledge, this is the first report of potential uncontrollable risks to patients caused by the fragile stereochemical structural effect of paclitaxel on metabolic stability.
语种中文
WOS记录号WOS:000265257500037
引用统计
文献类型会议论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/113470
专题中国科学院大连化学物理研究所
通讯作者Yang L(杨凌)
推荐引用方式
GB/T 7714
Zhang YY,Zhang JW,Ge GB,et al. Metabolism of 7-epi-paclitaxel by Human Cytochrome P450 Enzymes: Effect of Epimer-epimer Interaction on the Metabolic Elimination of Paclitaxel[C],2008:26/2.
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