Zegarska J, Hryniewiecka E, Zochowska D, Samborowska E, Jazwiec R, Maciej K, Nazarewski S, Dadlez M, Paczek L
Department of Immunology, Transplant Medicine and Internal Diseases, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland.
Department of Immunology, Transplant Medicine and Internal Diseases, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland; Department of Clinical Nursing, Medical University of Warsaw, Warsaw, Poland.
Transplant Proc. 2018 Sep;50(7):2235-2239. doi: 10.1016/j.transproceed.2018.03.025. Epub 2018 Mar 13.
Tacrolimus (Tac), an essential component of immunosuppressive therapy after solid-organ transplantation, has a narrow therapeutic index and requires therapeutic drug monitoring. Monitoring of Tac predose blood concentrations seems to be not always sufficient to avoid adverse effects. The aim of the study was to evaluate the levels of main Tac metabolites, 13-O-demethyl tacrolimus (13-DMT), 31-O-demethyl tacrolimus (31-DMT), and 15-O-demethyl tacrolimus (15-DMT), in kidney transplant recipients and to link them to clinical and biochemical parameters.
In 63 kidney transplant patients, concentrations of 13-DMT, 31-DMT, and 15-DMT were quantified using liquid chromatography combined with tandem mass spectrometry (LC/MS/MS).
None of the patients had detectable 31-DMT blood levels. There was a positive correlation between 13-DMT/Tac and alanine aminotransferase (ALAT) (r = 0.29, P = .046) and a negative correlation between 13-DMT/Tac and hemoglobin (r = -0.33, P = .008). Tac level did not correlate with ALAT nor with hemoglobin. There was no relationship between 13-DMT/Tac or 15-DMT/Tac and other biochemical or hematologic parameters or data, such as age, body mass index, arterial pressure, or time posttransplant. We observed significantly higher Tac concentrations in patients with hypercholesterolemia or hypertriglyceridemia compared with those without these comorbidities (6.45 ± 2.32 vs 5.16 ± 2.12 ng/mL, P = .043; 6.60 ± 2.30 vs 5.34 ± 2.20 ng/mL, P = .033, respectively).
Our data may reflect 13-DMT accumulation in liver dysfunction and higher Tac clearance in anemia. However, these results may suggest that 13-DMT/Tac ratio is a marker of myelotoxicity and hepatotoxicity. Further studies should be carried out to determine whether monitoring of 13-DMT could be beneficial in minimizing the adverse effects.
他克莫司（Tac）是实体器官移植后免疫抑制治疗的重要组成部分，其治疗指数较窄，需要进行治疗药物监测。监测他克莫司给药前血药浓度似乎并不总是足以避免不良反应。本研究的目的是评估肾移植受者体内主要他克莫司代谢产物13-O-去甲基他克莫司（13-DMT）、31-O-去甲基他克莫司（31-DMT）和15-O-去甲基他克莫司（15-DMT）的水平，并将它们与临床和生化参数联系起来。
在63例肾移植患者中，采用液相色谱串联质谱法（LC/MS/MS）对13-DMT、31-DMT和15-DMT的浓度进行定量分析。
所有患者的血药浓度均未检测到31-DMT。13-DMT/Tac与丙氨酸转氨酶（ALAT）呈正相关（r = 0.29，P = 0.046），与血红蛋白呈负相关（r = -0.33，P = 0.008）。他克莫司水平与ALAT和血红蛋白均无相关性。13-DMT/Tac或15-DMT/Tac与其他生化或血液学参数或数据（如年龄、体重指数、动脉压或移植后时间）之间无相关性。我们观察到，与无高胆固醇血症或高甘油三酯血症的患者相比，患有这些合并症的患者体内他克莫司浓度显著更高（分别为6.45±2.32 vs 5.16±2.12 ng/mL，P = 0.043；6.60±2.30 vs 5.34±2.20 ng/mL，P = 0.033）。
我们的数据可能反映了肝功能不全时13-DMT的蓄积以及贫血时他克莫司清除率的升高。然而，这些结果可能表明13-DMT/Tac比值是骨髓毒性和肝毒性的一个标志物。应开展进一步研究以确定监测13-DMT是否有助于将不良反应降至最低。
