CYP2C19基因多态性对侵袭性真菌感染重症患者伏立康唑血药浓度的影响

目的:研究CYP2C19基因多态性与侵袭性真菌感染重症患者伏立康唑标准化血药浓度的关系,为临床合理用药提供参考。方法:运用PCR-RFLP方法对患者CYP2C19 2(681G→A)和CYP2C19 3(636 G→A)位点进行基因型分析;使用HPLC法检测49名侵袭性真菌感染患者的伏立康唑血药浓度;并对伏立康唑血药浓度检测结果、药物疗效和不良反应与基因分型结果进行统计学分析。结果:49名患者中,同时分析CYP2C19两个位点,共有5种双位点基因型组合,包括强代谢型(extensive metabolizer,EM)的681GG-636GG、中等代谢型(intermediate metabolizer,IM)的681GA-636GG和681GG-636GA以及慢代谢型(poor metabolizer,PM)的681AA-636GG和681GA-636GA,其分布频率分别为14.29%,53.06%,8.16%,14.29%和10.2%。EM组、IM组和PM组的标准化血药浓度存在显著性差异(P<0.05),且PM组显著高于IM组,IM组显著高于EM组(P<0.05)。此外,基因多态性对各组间的药物疗效(P<0.05)和不良反应(P<0.05)均具有显著性影响。结论:CYP2C19基因多态性对伏立康唑血药浓度、疗效和不良反应产生显著影响,表明药物遗传学研究对伏立康唑临床合理用药具有重要的指导意义。

Effects of CYP2C19 gene polymorphism on plasma concentration of voriconazole in critically ill patients with invasive fungal infections

OBJECTIVE To determine effects of CYP2C19 gene polymorphism on standardized plasma concentration of voriconazole in critically ill patients with invasive fungal infections and provide reference for clinical rational medication.METHODS CYP2C19 variants (2 (681G→A) and 3 (636 G→A)) were detected using PCR-RFLP method and plasma concentration of voriconazole was determined by HPLC in 49 patients with invasive fungal infections. Concentration, drug effects and adverse reactions after treatment and genotypes were then statistically analyzed. RESULTS CYP2C19 2 and 3 were studied among 49 patients, the results showed that there were five genotypes of CYP2C19 gene in these subjects. There were 14.29% 681GG-636GG (extensive metabolizer, EM), 53.06% 681GA-636GG and 8.16% 681GG-636GA (intermediate metabolizer, IM), 14.29% 681AA-636GG and 10.2% 681GA-636GA (poor metabolizer, PM). Significant differences were observed in standardized plasma concentrations among EM, IM and PM groups (P<0.05, PM>IM>EM). Meanwhile, we found that there were significant differences between gene polymorphism and drug effects (P<0.05) and adverse reactions (P<0.05). CONCLUSION CYP2C19 polymorphism can significantly impact plasma concentration, effects and adverse reactions of voriconazole, indicating that pharmacogenetics is important for rationalized medication of voriconazole.