PDF(Pubmed)
Abstract：
Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes.
摘要：
伏立康唑是治疗和预防真菌感染的基石。虽然在预防性治疗期间CYP2C19基因型与伏立康唑暴露之间存在良好的相关性，在侵袭性曲霉病患者中没有发现相关性。促炎细胞因子导致CYP2C19酶活性的抑制(并且可能导致表型转化)。在这里，我们调查了炎症之间的关系，CYP2C19基因型预测表型，和CYP2C19活性的患者接受伏立康唑。数据来自两项研究伏立康唑治疗的前瞻性研究（NCT02074462和NCT00893555）。剂量校正的伏立康唑血浆浓度和C反应蛋白（CRP）被用作CYP2C19活性和炎症的替代因子，分别。经过数据提取和综合,可获得39例患者的配对伏立康唑和CRP测量数据.CYP2C19基因型预测代谢表型的分布为31％中间（IM），41%正常(NM)，和28%的快速代谢者(RM)。在炎症期间，剂量校正的伏立康唑水平增加了245%，278%,CYP2C19NMs和RM为486%，分别。具有中等或高CRP水平(>50mg/L)的患者被表型转化为较低代谢表型,而与他们的CYP2C19基因型无关。在对8名患者的亚组分析中，有或没有炎症的纵向数据，剂量校正的伏立康唑和CRP测量的模式相似，随着CRP水平降低或升高，CYP2C19活性降低。总之,伏立康唑的血浆浓度在炎症期间由于CYP2C19活性的下调而增加。虽然CYP2C19RM的这种影响似乎最大，CYP2C19基因型之间未观察到临床相关差异.
