Mendonza Anisha E, Zahir Hamim, Gohh Reginald Y, Akhlaghi Fatemeh
Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 41 Lower College Road, Kingston, RI 02881, USA.
Ther Drug Monit. 2007 Aug;29(4):391-8. doi: 10.1097/FTD.0b013e31811f319b.
The effect of diabetes mellitus on the pharmacokinetics of tacrolimus is not well characterized. We have compared tacrolimus 12-hour steady-state concentration-time profiles in diabetic (n = 11) and demographically matched nondiabetic (n = 9) stable kidney transplant recipients and derived a limited sampling strategy for the estimation of tacrolimus area under the concentration-time curve (AUC(0-12)). Tacrolimus concentration was measured by liquid chromatography tandem mass spectrometry and acetaminophen absorption method was used to characterize gastric emptying time. Demographic and biochemical characteristics were comparable between the two groups with the exception of significantly higher glycated hemoglobin levels in patients with diabetes (P = 0.02). Time to maximum concentration (T(max)) of acetaminophen was significantly longer in diabetics [D: 74.1 minute versus nondiabetics (ND): 29.3 minutes, P = 0.02]; however, tacrolimus T(max) was not significantly different (D: 121 minutes versus ND: 87 minutes, P = 0.15). Median (interquartile range) of tacrolimus AUC(0-12) was 114 (101-161) microghr/L in patients with diabetes and 113 (87-189) microghr/L in nondiabetics (P = 0.62). The following limited sampling equation [AUC(pred) (microghr/L) = 18.70 - 1.72 C(1 hr) - 4.09 C(2 hr) + 14.40 C(3 hr)] was derived from a training data set that included 10 patients. The correlation coefficient between model-predicted and observed AUC0-12 values was 0.999. Mean prediction error and root mean square error of the model-predicted values derived from the patients in validation data set were 0.04 and 17.48 microghr/L, respectively. In conclusion, it appears that diabetes has a modest effect on the rate but not the extent of tacrolimus absorption, and a three-point abbreviated sampling strategy common to both groups may prove useful for the estimation of tacrolimus exposure in kidney transplant recipients.
糖尿病对他克莫司药代动力学的影响尚未得到充分表征。我们比较了糖尿病（n = 11）和人口统计学匹配的非糖尿病（n = 9）稳定肾移植受者中他克莫司12小时稳态浓度-时间曲线，并推导了一种用于估计他克莫司浓度-时间曲线下面积（AUC(0-12)）的有限采样策略。通过液相色谱串联质谱法测量他克莫司浓度，并使用对乙酰氨基酚吸收法来表征胃排空时间。除糖尿病患者糖化血红蛋白水平显著更高外（P = 0.02），两组间人口统计学和生化特征具有可比性。糖尿病患者中对乙酰氨基酚达到最大浓度的时间（T(max)）显著更长[糖尿病组（D）：74.1分钟，非糖尿病组（ND）：29.3分钟，P = 0.02]；然而，他克莫司的T(max)无显著差异（D组：12分钟，ND组：87分钟，P = 0.15）。糖尿病患者中他克莫司AUC(0-12)的中位数（四分位间距）为114（101-161）μghr/L，非糖尿病患者中为113（87-189）μghr/L（P = 0.62）。以下有限采样方程[AUC(pred)（μghr/L）= 18.70 - 1.72 C(1小时) - 4.09 C(2小时) + 14.40 C(3小时)]源自一个包含10例患者的训练数据集。模型预测的和观察到的AUC0-12值之间的相关系数为0.999。验证数据集中患者的模型预测值的平均预测误差和均方根误差分别为0.04和17.48μghr/L。总之，糖尿病似乎对他克莫司的吸收速率有适度影响，但对吸收程度无影响，且两组通用的三点简化采样策略可能对估计肾移植受者中的他克莫司暴露有用。
