慢性髓性白血病患者体内细胞色素P450 3A同工酶活性及伊马替尼的药代动力学与治疗结果的关系
In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia.
作者信息
Skoglund Karin, Richter Johan, Olsson-Strömberg Ulla, Bergquist Jonas, Aluthgedara Warunika, Ubhayasekera S J Kumari A, Vikingsson Svante, Svedberg Anna, Söderlund Stina, Sandstedt Anna, Johnsson Anders, Aagesen Jesper, Alsenhed Jonas, Hägg Staffan, Peterson Curt, Lotfi Kourosh, Gréen Henrik
机构信息
*Division of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University; †Department of Hematology and Coagulation, Skåne University Hospital, Lund; ‡Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital; §Analytical Chemistry, Department of Chemistry-Biomedical Center and Science for Life Laboratory, Uppsala University; ¶Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm; ‖Department of Hematology, Linköping University Hospital; **Department of Internal Medicine, Motala Hospital; ††Department of Medicine, Ryhov County Hospital, Jönköping; ‡‡Department of Internal Medicine, Västervik Hospital; and §§Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
出版信息
Ther Drug Monit. 2016 Apr;38(2):230-8. doi: 10.1097/FTD.0000000000000268.
BACKGROUND
Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML.
METHODS
Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry.
RESULTS
Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity.
CONCLUSIONS
The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.
背景
细胞色素P450 3A（CYP3A）同工酶的代谢活性存在个体差异，因此可能影响慢性粒细胞白血病（CML）患者酪氨酸激酶抑制剂伊马替尼的治疗效果。本研究旨在探讨CYP3A代谢活性对CML患者伊马替尼血药浓度及治疗效果的影响。
方法
以奎宁作为探针药物，对43例CML患者进行CYP3A活性表型分析，并评估临床反应参数。采用液相色谱 - 质谱法测定伊马替尼及其主要代谢产物CGP74588的血药浓度。
结果
治疗12个月后对伊马替尼反应最佳的患者与反应不佳的患者相比，CYP3A活性无差异（奎宁代谢率分别为14.69和14.70；P = 0.966）。伊马替尼血药浓度和CGP74588/伊马替尼比值均与CYP3A活性无显著相关性。
结论
CYP3A活性不影响伊马替尼的血药浓度及治疗效果。这些结果表明，尽管伊马替尼由CYP3A酶代谢，但该活性并非伊马替尼代谢和排泄的限速步骤。未来的研究应聚焦于其他药代动力学过程，以确定导致伊马替尼血药浓度个体差异的主要因素。
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