Genetic Polymorphisms and Adverse Events on Unbound Imatinib and Its Active Metabolite Concentration in Patients With Gastrointestinal Stromal Tumors
Genetic Polymorphisms and Adverse Events on Unbound Imatinib and Its Active Metabolite Concentration in Patients With Gastrointestinal Stromal Tumors
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胃肠道间质瘤患者未结合伊马替尼及其活性代谢物浓度的基因多态性和不良事件
DOI：
10.3389/fphar.2019.00854
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发表时间：
2019-07
影响因子：
5.6
通讯作者：
Yong-Qing Wang
中科院分区：
文献类型：
--
作者：
Yi Qian;Lu-Ning Sun;Yang-Jie Liu;Qiang Zhang;Jianghao Xu;Zeng-Qing Ma;Xue-Hui Zhang;Hao Xu;Yong-Qing Wang
伊马替尼是治疗胃肠道间质瘤（GIST）的一线药物。本研究旨在探讨不同种类蛋白质浓度、代谢酶和药物转运体遗传多态性对未结合伊马替尼及其活性代谢物n -去甲基伊马替尼浓度的影响，以及药物不良反应（adr）与药物浓度的关系。对62例中国GIST患者进行5个单核苷酸多态性（snp）基因分型。采用LC-MS/MS联合平衡透析法测定GIST患者伊马替尼和n -去甲基伊马替尼的总浓度、未结合3h浓度和谷浓度。用一次性带插入物的红色平板分离未结合的药物。蛋白浓度越高，未结合伊马替尼和n -去甲基伊马替尼血浆浓度越高（p < 0.05）。rs755828176中GA基因型患者的未结合n -去甲基伊马替尼剂量调整谷血药浓度显著升高（p = 0.012）。rs3814055中CC基因型患者的非结合伊马替尼剂量调整谷血药浓度显著升高（p = 0.040）。adr组患者平均总伊马替尼C3h（3.10±0.96µg/ml）显著高于无adr组（p = 0.023）。adr患者n -去甲基-伊马替尼C3h（0.64±0.21µg/ml）的平均总量显著高于无adr患者（p = 0.004）。adr组未结合n -去甲基伊马替尼C3h平均值（6.49±2.53 ng/ml）显著高于无adr组（p = 0.042）。adr患者伊马替尼和n -去甲基伊马替尼的总C3h和未结合C3h均显著高于无adr患者（p < 0.05）。蛋白质浓度对未结合伊马替尼和n -去甲基伊马替尼浓度有很大影响。CYP3A4 rs755828176和NR1I2 rs3814055的遗传多态性与未结合伊马替尼和n -去甲基伊马替尼剂量调节槽血浆水平显著相关。GIST患者总伊马替尼和未结合伊马替尼或n -去甲基伊马替尼浓度也与不良反应显著相关。
Imatinib is a first-line drug for the treatment of gastrointestinal stromal tumors (GIST). This study aims to investigate the influence of different kinds of protein concentrations and genetic polymorphisms of metabolizing enzymes and drug transporters on unbound imatinib and its active metabolite N-desmethyl-imatinib concentration, as well as the relationship between adverse drug reactions (ADRs) and drug concentration. A total of 62 Chinese patients with GIST were genotyped for five single nucleotide polymorphisms (SNPs). Total and unbound 3h and trough concentration of imatinib and N-desmethyl-imatinib in GIST patients were determined by an LC-MS/MS method combined with an equilibrium dialysis. Single-Use Red Plate with inserts was used to separate the unbound drug. When the protein concentration became higher, the unbound imatinib and N-desmethyl-imatinib plasma concentration got higher (p < 0.05). Patients with GA genotype in rs755828176 had significantly higher unbound N-desmethyl-imatinib dose-adjusted trough plasma concentrations (p = 0.012). Patients with CC genotype in rs3814055 had significantly higher unbound imatinib dose-adjusted trough plasma concentrations (p = 0.040). The mean total imatinib C3h of patients with ADRs (3.10 ± 0.96 µg/ml) was significantly higher than that of patients without ADRs (p = 0.023). The mean total N-desmethyl-imatinib C3h of patients (0.64 ± 0.21 µg/ml) with ADRs was significantly higher than that of patients without ADRs (p = 0.004). The mean unbound N-desmethyl-imatinib C3h of patients with ADRs (6.49 ± 2.53 ng/ml) was significantly higher than that of patients without ADRs (p = 0.042). The total and unbound C3h of imatinib and N-desmethyl-imatinib in patients with ADRs was significantly higher than that in patients without ADRs (p < 0.05). Protein concentrations have great influence on the unbound imatinib and N-desmethyl-imatinib concentrations. The genetic polymorphisms of CYP3A4 rs755828176 and NR1I2 rs3814055 were significantly associated with unbound imatinib and N-desmethyl-imatinib dose-adjusted trough plasma levels. The total and unbound imatinib or N-desmethyl-imatinib concentration in patients with GIST was also significantly correlated with ADRs.
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影响因子：
3
作者：
Francis, Jose;Dubashi, Biswajit;Chandrasekaran, Adithan
通讯作者：
Chandrasekaran, Adithan
DOI：
--
发表时间：
2003
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
C. Gambacorti-Passerini;M. Zucchetti;D. Russo;R. Frapolli;M. Verga;S. Bungaro;L. Tornaghi;F. Rossi;P. Pioltelli;E. Pogliani;D. Alberti;G. Corneo;M. D’Incalci
通讯作者：
C. Gambacorti-Passerini;M. Zucchetti;D. Russo;R. Frapolli;M. Verga;S. Bungaro;L. Tornaghi;F. Rossi;P. Pioltelli;E. Pogliani;D. Alberti;G. Corneo;M. D’Incalci
影响因子：
3.4
作者：
Widmer, N.;Decosterd, L. A.;Buclin, T.
通讯作者：
Buclin, T.
DOI：
10.1007/978-3-642-54490-3_1
发表时间：
2014-01-01
期刊：
SMALL MOLECULES IN ONCOLOGY, 2ND EDITION
影响因子：
--
作者：
Waller, Cornelius F.
通讯作者：
Waller, Cornelius F.
影响因子：
2.5
作者：
Yukari Miyadera;T. Naito;Takahiro Yamada;J. Kawakami
通讯作者：
Yukari Miyadera;T. Naito;Takahiro Yamada;J. Kawakami