Department of Medical and Health Sciences, Linköping University, Sweden.
Eur J Clin Pharmacol. 2010 Apr;66(4):383-6. doi: 10.1007/s00228-009-0772-y.
Imatinib is currently used for the treatment of chronic myeloid leukemia (CML). The main metabolite CGP74588 has similar potency to that of imatinib and is a product of CYP3A4 and CYP3A5 metabolism. However, the clinical significance of the metabolism on therapeutic response and pharmacokinetics is still unclear. We designed this study to investigate the role of the CYP3A activity in the response to imatinib therapy.
Fourteen CML patients were phenotyped for in vivo CYP3A activity using quinine as a probe drug. The plasma concentration ratio of quinine and its CYP3A metabolite was used for assessing CYP3A activity. The patients were divided into complete molecular responders with undetectable levels of BCR-ABL transcripts after 12 months of therapy and into partial molecular responders who had failed to achieve a complete molecular response.
Patients that achieved complete molecular response showed significantly (Mann-Whitney U-test, p=0.013) higher in vivo CYP3A activity (median quinine metabolic ratio = 10.1) than patients achieving partial molecular response (median = 15.9).
These results indicate a clinical significance of the CYP3A activity and its metabolic products in CML patients treated with imatinib.
伊马替尼目前被用于治疗慢性髓性白血病（CML）。主要代谢产物 CGP74588 与伊马替尼具有相似的效力，是 CYP3A4 和 CYP3A5 代谢的产物。然而，代谢物对治疗反应和药代动力学的临床意义尚不清楚。我们设计了这项研究，旨在探讨 CYP3A 活性在伊马替尼治疗反应中的作用。
14 名 CML 患者使用奎宁作为探针药物进行体内 CYP3A 活性表型分析。使用奎宁及其 CYP3A 代谢物的血浆浓度比值来评估 CYP3A 活性。将患者分为在治疗 12 个月后 BCR-ABL 转录物水平无法检测到的完全分子反应者和未能实现完全分子反应的部分分子反应者。
达到完全分子反应的患者体内 CYP3A 活性（中位数奎宁代谢比=10.1）明显高于达到部分分子反应的患者（中位数=15.9）（Mann-Whitney U 检验，p=0.013）。
这些结果表明 CYP3A 活性及其代谢产物在接受伊马替尼治疗的 CML 患者中具有临床意义。
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