Department of Microbiology and Immunology, KU Leuven - University of Leuven, Leuven, Belgium.
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
Br J Clin Pharmacol. 2017 Nov;83(11):2406-2415. doi: 10.1111/bcp.13343. Epub 2017 Jul 14.
The CYP3A metric 4β-hydroxycholesterol (4βOHC) has been shown to correlate with tacrolimus steady-state apparent oral clearance (CL/F). Recently, pretransplant 4βOHC was shown not to predict tacrolimus CL/F after transplantation in a cohort of renal recipients (n = 79). The goal of the current study was determine whether these findings could be validated in a substantially larger cohort.
In a retrospective analysis of 279 renal recipients, tacrolimus trough concentrations (C0), daily dose, haematocrit and other relevant covariates were registered every day for the first 14 days after transplantation. 4βOHC and cholesterol were quantified on plasma collected immediately pretransplant using liquid chromatography tandem-mass spectrometry. Patients were genotyped for CYP3A51 and CYP3A422.
A total of 3551 tacrolimus C0 concentrations were registered. In a linear mixed model for the 14-day period, determinants of tacrolimus C0 were CYP3A5 genotype, haematocrit, age and weight (overall R = 0.179). Determinants of daily dose were CYP3A5 genotype, age, methylprednisolone dose, tacrolimus formulation, ALT and estimated glomerular filtration rate (overall R = 0.242). Considering each of the first 5 days separately, 4βOHC had a limited effect on tacrolimus C0 on day 3 only (-1.00 ng ml per ln, P = 0.035) but not on any other day, and no effect on dose or C0/dose. During the first 5 days, haematocrit and age, which were previously established as determinants of tacrolimus disposition under steady-state conditions, never explained more than 17.7% of between-subject variability in tacrolimus C0/dose.
The CYP3A metric 4βOHC cannot be used to predict tacrolimus dose requirements in the first days after transplantation.
CYP3A 标志物 4β-羟基胆固醇（4βOHC）与他克莫司稳态口服清除率（CL/F）相关。最近，在一组肾移植受者（n=79）中，移植前的 4βOHC 并未预测移植后他克莫司 CL/F。本研究的目的是确定这些发现是否可以在更大的队列中得到验证。
对 279 例肾移植受者进行回顾性分析，在移植后第 14 天内每天登记他克莫司谷浓度（C0）、每日剂量、红细胞压积和其他相关协变量。使用液相色谱串联质谱法在移植前即刻采集的血浆中定量测定 4βOHC 和胆固醇。对 CYP3A51 和 CYP3A422 进行基因分型。
共登记了 3551 个他克莫司 C0 浓度。在 14 天期间的线性混合模型中，他克莫司 C0 的决定因素是 CYP3A5 基因型、红细胞压积、年龄和体重（总体 R=0.179）。每日剂量的决定因素是 CYP3A5 基因型、年龄、甲泼尼龙剂量、他克莫司制剂、ALT 和估计肾小球滤过率（总体 R=0.242）。分别考虑前 5 天中的每一天，只有第 3 天 4βOHC 对他克莫司 C0 有有限的影响（-1.00ng/ml per ln，P=0.035），而对其他任何一天都没有影响，也对剂量或 C0/剂量没有影响。在前 5 天中，红细胞压积和年龄是在稳态条件下确定的他克莫司处置的决定因素，从未解释过他克莫司 C0/剂量的个体间变异性的 17.7%以上。
CYP3A 标志物 4βOHC 不能用于预测移植后最初几天的他克莫司剂量需求。
