Zhong W, Zhang Y, Zhang M-Z, Huang X-H, Li Y, Li R, Liu Q-W
Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
Pediatric Clinical Pharmacology Laboratory, Department of Anesthesiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Clin Pharm Ther. 2018 Jun;43(3):414-421. doi: 10.1111/jcpt.12652. Epub 2017 Dec 16.
The primary objective of this study was to compare the pharmacokinetics of dexmedetomidine in patients with end-stage renal failure and secondary hyperparathyroidism with those in normal individuals.
Fifteen patients with end-stage renal failure and secondary hyperparathyroidism (Renal-failure Group) and 8 patients with normal renal and parathyroid gland function (Control Group) received intravenous 0.6 μg/kg dexmedetomidine for 10 minutes before anaesthesia induction. Arterial blood samples for plasma dexmedetomidine concentration analysis were drawn at regular intervals after the infusion was stopped. The pharmacokinetics were analysed using a nonlinear mixed-effect model with NONMEM software. The statistical significance of covariates was examined using the objective function (-2 log likelihood). In the forward inclusion and backward deletion, covariates (age, weight, sex, height, lean body mass [LBM], body surface area [BSA], body mass index [BMI], plasma albumin and grouping factor [renal failure or not]) were tested for significant effects on pharmacokinetic parameters. The validity of our population model was also evaluated using bootstrap simulations.
The dexmedetomidine concentration-time curves fitted best with the principles of a two-compartmental pharmacokinetic model. No covariate of systemic clearance further improved the model. The final pharmacokinetic parameter values were as follows: V = 60.6 L, V = 222 L, Cl = 0.825 L/min and Cl = 4.48 L/min. There was no influence of age, weight, sex, height, LBM, BSA, BMI, plasma albumin and grouping factor (renal failure or not) on pharmacokinetic parameters. Although the plasma albumin concentrations (35.46 ± 4.13 vs 44.10 ± 1.12 mmol/L, respectively, P < .05) and dosage of propofol were significantly lower in the Renal-failure Group than in the Control Group (81.68 ± 18.08 vs 63.07 ± 13.45 μg/kg/min, respectively, P < .05), there were no differences in the context-sensitive half-life and the revival time of anaesthesia between the 2 groups.
The pharmacokinetics of dexmedetomidine were best described by a two-compartment model in our study. The pharmacokinetic parameters of dexmedetomidine in patients with end-stage renal failure and hyperparathyroidism were similar to those in patients with normal renal function. Further studies of dexmedetomidine pharmacokinetics are recommended to optimize its clinical use.
本研究的主要目的是比较右美托咪定在终末期肾衰竭合并继发性甲状旁腺功能亢进患者与正常个体中的药代动力学。
15例终末期肾衰竭合并继发性甲状旁腺功能亢进患者（肾衰竭组）和8例肾功能及甲状旁腺功能正常的患者（对照组）在麻醉诱导前10分钟静脉注射0.6μg/kg右美托咪定。输注停止后，定期采集动脉血样进行血浆右美托咪定浓度分析。使用NONMEM软件通过非线性混合效应模型分析药代动力学。使用目标函数（-2对数似然值）检验协变量的统计学意义。在向前纳入和向后删除过程中，测试协变量（年龄、体重、性别、身高、瘦体重[LBM]、体表面积[BSA]、体重指数[BMI]、血浆白蛋白和分组因素[是否肾衰竭]）对药代动力学参数的显著影响。还使用自抽样模拟评估了我们总体模型的有效性。
右美托咪定浓度-时间曲线最符合二室药代动力学模型的原理。全身清除率的协变量未进一步改善模型。最终药代动力学参数值如下：V = 60.6L，V = 222L，Cl = 0.825L/min，Cl = 4.48L/min。年龄、体重、性别、身高、LBM、BSA、BMI、血浆白蛋白和分组因素（是否肾衰竭）对药代动力学参数无影响。尽管肾衰竭组的血浆白蛋白浓度（分别为35.46±4.13与44.10±1.12mmol/L，P <.05）和丙泊酚剂量显著低于对照组（分别为81.68±18.08与63.07±13.45μg/kg/min，P <.05），但两组之间的时效半衰期和麻醉苏醒时间无差异。
在我们的研究中，右美托咪定的药代动力学最好用二室模型描述。终末期肾衰竭和甲状旁腺功能亢进患者中右美托咪定的药代动力学参数与肾功能正常患者相似。建议进一步研究右美托咪定的药代动力学以优化其临床应用。
