Bressolle F, Rochette A, Khier S, Dadure C, Ouaki J, Capdevila X
Pharmacokinetic Laboratory, Faculty of Pharmacy, Montpellier I University, BP 14491, 15 Avenue Ch. Flahault, 34093 Montpellier Cedex 5, France.
Br J Anaesth. 2009 Mar;102(3):390-9. doi: 10.1093/bja/aen405. Epub 2009 Feb 3.
Few data are available on the stereoselective pharmacokinetics of tramadol in children. The aim of this study was to develop a population pharmacokinetic model for the (+)- and (-)-enantiomers of tramadol and its O-demethyl tramadol metabolite (M1) in children.
Twenty-five children (1-8 yr) were included in this study. Tramadol was administered after surgery by continuous infusion (loading dose, 2 mg kg(-1) i.v. over 10 min followed by continuous infusion of 8 mg kg(-1) over 24 h). If pain relief was inadequate, additional 1 mg kg(-1) i.v. bolus doses of tramadol were given over 10 min. A two-compartment structural model was used with NONMEM.
For both enantiomers of tramadol, weight was the only patient characteristic parameter showing significant covariate effects on clearance (CL). CL increased by 5.7-6.1 litre h(-1) between 8-12 and 13-16 kg, and by 2.4-3.3 litre h(-1) between 13-16 and 17-33 kg. The rate constants associated with the metabolite elimination [0.144 h(-1), (+)-M1 and 0.18 h(-1), (-)-M1] were smaller than the elimination rate constants of the parent drugs [0.243 h(-1), (+)-tramadol and 0.241 h(-1), (-)-tramadol], suggesting that the metabolite disposition was rate-limited by its elimination. The presence of two subpopulations of patients was suspected on the basis of the observed bimodal distributions of the AUC(M1)/AUC(tramadol) ratios.
The results of this study combine relationships between tramadol CL and patient covariates that may be useful for dose adjustment. Polymorphism is likely to contribute to the interpatient variability observed in the AUC M1/AUC tramadol ratios.
关于曲马多在儿童体内的立体选择性药代动力学的数据很少。本研究的目的是建立儿童曲马多（+）-和（-）-对映体及其O-去甲基曲马多代谢物（M1）的群体药代动力学模型。
本研究纳入了25名儿童（1 - 8岁）。术后通过持续输注给予曲马多（负荷剂量，静脉注射2 mg·kg⁻¹，持续10分钟，随后在24小时内持续输注8 mg·kg⁻¹）。如果镇痛效果不佳，则在10分钟内额外静脉注射1 mg·kg⁻¹的曲马多推注剂量。使用两室结构模型和NONMEM进行分析。
对于曲马多的两种对映体，体重是唯一对清除率（CL）显示出显著协变量效应的患者特征参数。CL在8 - 12 kg与13 - 16 kg之间增加了5.7 - 6.1升·小时⁻¹，在13 - 16 kg与17 - 33 kg之间增加了2.4 - 3.3升·小时⁻¹。与代谢物消除相关的速率常数[0.144小时⁻¹，（+）-M1和0.18小时⁻¹，（-）-M1]小于母体药物的消除速率常数[0.243小时⁻¹，（+）-曲马多和0.241小时⁻¹，（-）-曲马多]，这表明代谢物的处置受其消除的速率限制。根据观察到的AUC（M1）/AUC（曲马多）比值的双峰分布，怀疑存在两个患者亚群。
本研究结果结合了曲马多CL与患者协变量之间的关系，这可能有助于剂量调整。多态性可能是导致AUC M1/AUC曲马多比值中观察到的患者间变异性的原因。
