Composite CYP3A phenotypes influence tacrolimus dose-adjusted concentration in lung transplant recipients.
Composite CYP3A phenotypes influence tacrolimus dose-adjusted concentration in lung transplant recipients.
复制标题
复合CYP3A表型影响肺移植受者他克莫司剂量调整浓度
DOI：
10.1097/fpc.0000000000000472
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发表时间：
2022-07-01
影响因子：
2.6
通讯作者：
Van Driest, Sara L.
中科院分区：
文献类型：
--
作者：
Liu, Michelle;Shaver, Ciara M.;Birdwell, Kelly A.;Heeney, Stephanie A.;Shaffer, Christian M.;Van Driest, Sara L.
关键词：
他克莫司药代动力学的患者间变异性归因于细胞色素P-450 3A 4/5同工酶（由CYP 3A 4和CYP 3A 5编码）的代谢。基于CYP 3A 5检测结果调整他克莫司的指南已发表;然而，CYP 3A 4变体也会导致他克莫司药代动力学的变异性。尚未评价合并CYP 3A 5和CYP 3A 4增加（*1G，*1B）和减少（*22）功能变体的复合表型的影响。本研究的目的是研究功能增加和减少的CYP 3A变体对体重和剂量调整的他克莫司浓度（C 0/D）的影响。我们对肺移植受者进行了一项单中心回顾性队列研究，以评估在索引移植住院期间复合CYP 3A表型组的中位他克莫司C 0/D。使用CYP 3A 4和CYP 3A 5等位基因将患者从最低到最高CYP 3A活性分为4个CYP 3A组。还评估了ABCB 1和其他候选基因的探索性分析。在纳入的92例个体中，大多数（58例）为CYP 3A第2组。CYP 3A组之间的中位他克莫司C 0/D存在显著差异（p=0.0001）。CYP 3A组2中位他克莫司C 0/D为190.5 [四分位距（147.6-267.5）]（ng/mL）/（mg/kg/d），显著高于组4 [107.9（90.4-116.1），p=0.0001）]。第2组中位他克莫司C 0/D与第1组和第3组无显著差异[分别为373.5（149.2-490.3）和81.4（62.6-184.1）]。ABCB 1双倍型的他克莫司C 0/D无显著差异。这些数据表明，除了CYP 3A 5外，复合CYP 3A表型还包括CYP 3A 4的增加和减少的变异信息，可能会显著影响术后早期他克莫司的C 0/D。
Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A4/5 isoenzymes (encoded by CYP3A4 and CYP3A5). Guidelines for adjusting tacrolimus based on CYP3A5 test results are published; however, CYP3A4 variants also contribute to the variability in tacrolimus pharmacokinetics. The effects of composite phenotypes incorporating CYP3A5 and CYP3A4 increased (*1G, *1B) and decreased (*22) function variants have not been evaluated. The objective of this study is to investigate the impact of both increased and decreased function CYP3A variants on weight and dose-adjusted tacrolimus concentration (C0/D). We performed a single-center retrospective cohort study of lung transplant recipients to evaluate the median tacrolimus C0/D by composite CYP3A phenotype groups during the index transplant hospitalization. CYP3A4 and CYP3A5 alleles were used to classify patients into four CYP3A groups from least to most CYP3A activity. Exploratory analyses of ABCB1 and additional candidate genes were also assessed. Of the 92 included individuals, most (58) were CYP3A Group 2. The median tacrolimus C0/D differed significantly between CYP3A groups (p=0.0001). CYP3A Group 2 median tacrolimus C0/D was 190.5 [interquartile range (147.6-267.5)] (ng/mL)/(mg/kg/d) and significantly higher than Group 4 [107.9 (90.4-116.1), p=0.0001)]. Group 2 median tacrolimus C0/D did not significantly differ from Group 1 and Group 3 [(373.5 (149.2-490.3) and 81.4 (62.6-184.1), respectively]. No significant differences in tacrolimus C0/D were found for the ABCB1 diplotypes. These data indicate that a composite CYP3A phenotype incorporating both increased and decreased variant information from CYP3A4 in addition to CYP3A5 may significantly influence tacrolimus C0/D during the early postoperative period.