白血病患者伏立康唑血药浓度监测的回顾性研究

A retrospective study of plasma concentration of voriconazole in leukemia patients

目的探讨白血病患者伏立康唑血药浓度、基因代谢型及G、GM实验结果的关联性。方法建立测定伏立康唑血药浓度的高效液相色谱串联质谱法(HPLC-MS/MS),并利用MATLAB软件对所测血药浓度进行分析,开展G、GM实验,采用t检验比较2种实验结果为阳性和阴性的患者伏立康唑的血药浓度值;使用DNA序列测定法检测CYP2C19*2和CYP2C9*3基因代谢型并探讨其与伏立康唑血药浓度的关联性。结果所有患者伏立康唑血药浓度的平均值为(1.47±1.35)μg/ml,伏立康唑在白血病患者中的有效血药浓度为0.44~2.49μg/ml;G、GM实验阳性的患者伏立康唑血药浓度均小于G、GM实验阴性的患者[(1.32±1.21)μg/ml vs(2.25±1.20)μg/ml;(1.27±0.92)μg/mlvs(2.15±0.81)μg/ml],且差异具有统计学意义(t=-2.941,P=0.032;t=-12.674,P=0.001);CYP2C19*2基因代谢型杂合弱代谢基因型GA的血药浓度值高于野生型正常代谢型GG[(1.42±1.13)μg/ml vs(1.30±1.40)μg/ml],但差异无统计学意义(t=-1.689,P=0.129);CYP2C9*3基因代谢型杂合弱代谢基因型AC的血药浓度值高于野生型正常代谢型AA[(2.30±2.05)μg/ml vs(1.43±1.15)μg/ml],差异具有统计学意义(t=12.386,P=0.006)。结论白血病患者伏立康唑血药浓度、基因代谢型及G、GM实验阳性存在一定的关联性即患者伏立康唑弱代谢基因型,伏立康唑血药浓度高;患者G、GM实验阳性,伏立康唑血药浓度低。

Objective To analyze the correlation of plasma concentration of voriconazole with the genotype of drug metabolism genes and（1–3）-β-D glucan（G） and glactomannan（GM） tests in leukemia patients to provide a reference for rational clinical application of voriconazole. Methods Plasma concentration of voriconazole was determined using high performance liquid chromatography tandem mass spectrometry（HPLC-MS/MS） and software MATLAB software. G and GM tests were used to detect fungal infection and to explore whether fungal infection was correlated with the concentration of voriconazole. CYP2 C19＊2 and CYP2 C9＊3 genes were genotypes using DNA sequence metabotropic assays to explore whether the genotype was correlated with the concentration of voriconazole. Results The mean plasma concentration of voriconazole determined by HPLC-MS/MS analysis was（1.47±1.35） μg/mL, and the range of the effective concentration was 0.44-2.49 μg/mL. The concentration of voriconazole in the G/GM test-positive group was significantly lower than that in the negative group [（1.32±1.21） μg/ml vs（2.25±1.20） μg/ml;（1.27±0.92） μg/ml vs（2.15±0.81） μg/ml], the difference is statistically significant（t=-2.941, P=0.032; t=-12.674, P=0.001）. The concentration of voriconazole in the CYP2 C19＊2（GA） group was greater than that in the CYP2 C19＊2（GG） [（1.42±1.13） μg/ml vs（1.30±1.40） μg/ml], but there was no significant difference（t=-1.689, P=0.129）. The concentration of voriconazole in the CYP2 C9＊3（AC） group was significantly greater than that in the CYP2 C9＊3（AA） group（t=12.386, P=0.006）. Conclusion The concentration of voriconazole correlates with the genotype of CYP2 C19＊2 and CYP2 C9＊3 genes and G and GM tests in leukemia patients. The concentration of voriconazole is high in patients with voriconazole weakly metabolized genotype, and is low in patients with positive G and GM tests.