Madsen Mads Juul, Bergmann Troels K, Brøsen Kim, Thiesson Helle Charlotte
Department of Nephrology, Odense University Hospital, J B WinslowsVej 19, 5000, Odense C, Denmark.
Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
Drugs R D. 2017 Jun;17(2):279-286. doi: 10.1007/s40268-017-0177-9.
Tacrolimus is a calcineurin inhibitor used as an immunosuppressant drug in solid organ transplantation, and is mainly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. Studies have shown an association between the CYP3A5 genotype and tacrolimus dose-adjusted trough concentrations. Variants in the genes PPARA, POR and CYP3A4 have recently been shown to influence tacrolimus metabolism. Furthermore, pharmacokinetic interaction between corticosteroid treatment and tacrolimus has been shown. In the present study, we investigated a potential association between CYP3A53, PPARA c.209-1003G>A, POR28 and CYP3A4*22 and dose-adjusted tacrolimus trough concentrations in a primarily corticosteroid-free (>85%) population of Danish pediatric and adult kidney transplant recipients.
Seventy-two patients receiving treatment with oral tacrolimus were genotyped using real-time polymerase chain reaction and Primer-Probe Detection. Tacrolimus trough concentrations, corresponding doses and covariates were retrospectively collected from the patients' medical charts.
It was confirmed that CYP3A51 wild-type carriers had lower median dose-adjusted tacrolimus trough concentrations compared with noncarriers. Adults had 56 and 77% lower trough concentrations at 6 weeks (p = 0.0003) and 1 year, respectively (p < 0.0017), and, similarly, children had 65 and 39% lower median concentrations, with p values of 0.006 and 0.011, respectively. No association was found for PPARA c.209-1003G>A, POR28, or CYP3A4*22. An association between the PPARA c.209-1003G>A genotype and an increased number of infections with cytomegalovirus (CMV) within the first year was identified (p < 0.05). Only 29% of trough concentrations measured between 2 and 12 weeks post-transplantation were on target.
This study shows that the known association of the CYP3A5 genotype with tacrolimus dose-adjusted trough concentrations has the same impact in a corticosteroid-sparse population. The association between PPARA variance and infections with CMV will need further investigation.
他克莫司是一种钙调神经磷酸酶抑制剂，在实体器官移植中用作免疫抑制剂药物，主要通过细胞色素P450（CYP）3A4和CYP3A5代谢。研究表明CYP3A5基因分型与他克莫司剂量调整后的谷浓度之间存在关联。最近发现PPARA、POR和CYP3A4基因中的变异会影响他克莫司的代谢。此外，已表明皮质类固醇治疗与他克莫司之间存在药代动力学相互作用。在本研究中，我们调查了在丹麦儿科和成人肾移植受者中主要无皮质类固醇（>85%）的人群中，CYP3A53、PPARA c.209-1003G>A、POR28和CYP3A4*22与剂量调整后的他克莫司谷浓度之间的潜在关联。
使用实时聚合酶链反应和引物-探针检测对72例接受口服他克莫司治疗的患者进行基因分型。从患者的病历中回顾性收集他克莫司谷浓度、相应剂量和协变量。
证实CYP3A51野生型携带者的剂量调整后的他克莫司谷浓度中位数低于非携带者。成人在6周时谷浓度分别降低56%和77%（p = 0.0003），在1年时分别降低（p < 0.0017），同样，儿童的中位数浓度分别降低65%和39%，p值分别为0.006和0.011。未发现PPARA c.209-1003G>A、POR28或CYP3A4*22存在关联。确定PPARA c.209-1003G>A基因型与第一年巨细胞病毒（CMV）感染数量增加之间存在关联（p < 0.05）。移植后2至12周测量的谷浓度中只有29%达到目标值。
本研究表明，已知的CYP3A5基因型与他克莫司剂量调整后的谷浓度之间的关联在皮质类固醇缺乏的人群中具有相同的影响。PPARA变异与CMV感染之间的关联需要进一步研究。
