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学科主题: 物理化学
题名: Metabolism of 7-epi-paclitaxel by Human Cytochrome P450 Enzymes: Effect of Epimer-epimer Interaction on the Metabolic Elimination of Paclitaxel
作者: 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
出版日期: 2008-05-11
会议地点: 中国
通讯作者: 杨凌
ISSN: 0360-2532
部门归属: 十八室
主办者: DRUG METABOLISM REVIEWS
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
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内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/113470
Appears in Collections:中国科学院大连化学物理研究所_会议论文

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Recommended Citation:
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]. 见:2nd ASIAN PACIFIC REGIONAL ISSX MEETING. 中国. 2008-5-11.
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