严重烧伤家兔不同病理期丙泊酚的药代动力学差异

Pharmacokinetics differences of propofol during different pathological stages of severe burn in rabbits

目的了解严重烧伤家兔在休克期与高代谢期丙泊酚的药代动力学特征和差异。方法将20只新西兰大白兔按随机数字表法分为烧伤组和假伤组，每组10只。将烧伤组家兔造成30％TBSA的Ⅲ度烫伤（以下称烧伤），伤后即刻复苏；6h后静脉注射5．1mg／kg丙泊酚，分别于注药后1、3、5、10、15、20、30、45、60、90min于左侧颈外静脉取血1，5mL；1周后重复上述注药及标本采集过程。假伤组家兔除致假伤外，其他处理同烧伤组。用高效液相色谱仪集中检测2组家兔血浆丙泊酚浓度，采用3P97实用药代动力学计算程序处理血浆药物浓度一时间数据，拟合药代动力学模型并求算参数。结果烧伤组家兔药物浓度一时间数据符合二房室模型，假伤组符合三房室模型。休克期，与假伤组家兔中央室分布容积[Vc，（3．1±1．5）L／kg]、曲线下面积[AUC，（25±7）mg·min·L^-1]、消除相半衰期[t1／2β，（113±93）min]、总清除率[CLs，（110±50）mL·kg^-1·min^-1]比较，烧伤组Vc[（8．8±4．2）L／kg]与AUC[（44±10）mg·min·L^-1]增大（t值分别为3．191与3．668，P值均小于0．01），t1／2β[（339±258）min]延长（t=2．932，P〈0．05），CLs[（40±30）mL·kg^-1·min^-1]降低（t=-3．013，P〈0．05）。高代谢期，烧伤组家兔CLs[（180±40）mL·kg^-1·min^-1]显著高于假伤组[（90±30）mL·kg^-1·min^-1，t=-3．013，P〈0．05]。与本组休克期比较，烧伤组家兔高代谢期Vc[（4．1±1．3）L／kg]与AUC[（24±5）mg·min·L^-1]显著减小（t值分别为2．979与3．766，P值均小于0．01），分布相半衰期[t1／2α，休克期为（16．1±13．1）min、高代谢期为（8．3±2．5）min]、t1／2β[（55±19）min]明显缩短（t值分别为9．065与8．795，P值均小于0．01），而CLs则显著增加（t=4．238，P〈0．01）。结论严重烧伤家兔休克期与高代谢期丙泊酚药代动力学差异较大，休克期以Ve、AUC增大，t1／2α、t1／2β延长，CLs降低为特点；高代谢期以CLs显著增加为特点。

Objective To investigate the characteristics and differences of propofol pharmacokinetics in shock phase and hypermetabolic phase in severe burn in rabbits. Methods Twenty New Zealand rabbits were assigned to burn group （ n = 10） and sham injury group （ n = 10） according to the random number table. Rabbits in burn group were inflicted with 30% TBSA full-thickness scald （ named burn below） , resuscitated instantly, and were intravenously injected with 5.1 mg/kg propofol 6 hours after injury. 1.5 mL blood was collected from left external jugular vein at 1 , 3, 5, 10, 15, 20, 30, 45, 60, 90 minute （s） after injection respectively. Above procedure was performed again 1 week later. Rabbits in sham injury group were treated similarily as rabbits in burn group but were sham scalded. Propofol concentration in plasma was determined with high performance liquid chromatography. Data of propofol concentration-time were analyzed with 3P97 practical pharmacokinetics calculating program, and then the most fit compartment model was selected to calculate pharmacokinetic parameters. Results The blood concentration-time curve of propofol fitted in with the two-compartment model in burn group, and three-compartment model in sham injury group. During shock phase, comparing with central compartment distribution volume [ Vc, （3.1 ± 1.5 ） L/kg], area under curve [AUC, （25±7） mg·kg^-1·min^-1, elimination phase half life [t1/2β, （113 ±93） mini, clearance [CLs, （110±50） mL·kg^-1·min^-1 of rabbits in sham injury group, Vc[（8.8 ± 4.2） L · kg^-1] and AUC [ （44 ± 10 ）mg ·min ·L^-1 increased significantly （ with t value respectively 3. 191 and 3. 668, and P values both below 0.01 ） ; tl/2/3 [ （339 ± 258） rain J prolonged （ t = 2. 932, P 〈 0. 05）; CLs [（40-±30） mL·kg^-1·min^-1] decreased （ t =-3.013, P 〈0.05） in burn group. During hypermetabolic phase, CLs[ （ 180 ± 40） mL·kg^-1·min^-1] of rabbits in burn group was significantly higher than that in sham injury group [（90 ±30） mL ·kg^-1·min^-1, t = -3.013, P 〈0.05]. Comparing with those of rabbits in burn group during shock phase, Vc [ （4.1 ±1.3） L/g] and AUC [ （24 ±5） mg·min·L^-1] decreased significantly （ with t value respectively 2. 979 and 3. 766, and P value both below 0. 01 ） ; distribution phase half time [ t1/2α, shock phase （ 16.1 ± 13.1 ） rain and hypermetabolic phase （8.3 ± 2.5 ） min ] and tl/2β [ （ 55 ± 19 ）min ] shortened obviously （ with t value respectively 9. 065 and 8. 795, and P values both below 0.01 ） ; CLs increased significantly （ t =4. 238, P 〈0.01 ） during hypermetabolic phase. Conclusions There are great differences in propofol pharmacokinetics between shock phase and hypermetabolic phase in severely burned rabbits. The change is characterized by increase in Vc and AUC, extension of tl/2α and tl/2β, decrease in CLs during shock phase and obvious increase of CLs during hypermetabolic phase.