参与CYP2C8和CYP3A4的去伊马替尼在人类肝微粒体。
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d 'Esposito F Nebot N, Crettol年代,Tattam B,希布斯DE,穆雷M
参与CYP2C8和CYP3A4的去伊马替尼在人类肝微粒体。
Br J杂志。2010年11月,161 (5):1059 - 69。doi: 10.1111 / j.1476-5381.2010.00946.x。
- PubMed ID
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20977456 (在PubMed]
- 文摘
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背景和目的:伊马替尼是一个临床上重要的酪氨酸激酶抑制剂特异表达在慢性粒细胞白血病和胃肠道间质肿瘤。Inter-individual伊马替尼药物动力学的变化是广泛的,药物安全性和有效性的影响。肝细胞色素P450 (CYP) 3 a4去甲基化与伊马替尼,但伊马替尼的间隙减少在长期治疗。CYP3A表型与伊马替尼间隙在开始治疗,但不是在稳定状态。本研究评估多个cyp的可能性可能导致伊马替尼在肝脏氧化。实验方法:伊马替尼生物转化在人类肝微粒体(n = 20)和cDNA-expressed cyp由质决定。伊马替尼之间的关系去和其他药物代谢cyp评估。主要结果:N-desmethylimatinib形成与微粒体氧化的CYP3A4基质睾酮(ρ= 0.60;P < 0.01)和咪达唑仑(ρ= 0.46;P < 0.05), CYP2C8衬底紫杉醇(ρ= 0.58; P < 0.01). cDNA-derived CYPs 2C8, 3A4, 3A5 and 3A7 supported imatinib N-demethylation, but 10 other CYPs were inactive; in kinetic studies, CYP2C8 was a high-affinity enzyme with a catalytic efficiency approximately 15-fold greater than those of CYPs 3A4 and 3A5. The CYP3A inhibitors ketoconazole and troleandomycin, and the CYP2C8 inhibitors quercetin and paclitaxel decreased imatinib oxidation. From molecular modelling, the imatinib structure could be superimposed on a pharmacophore for CYP2C8 substrates. CONCLUSIONS AND IMPLICATIONS: CYP2C8 and CYPs 3A contribute to imatinib N-demethylation in human liver. The involvement of CYP2C8 may account in part for the wide inter-patient variation in imatinib pharmacokinetics observed in clinical practice.
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- 药物反应
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