The Research Of Paracetamol's PK-PD Model After Acupoint Injection

Objective: To study the paracetamol' s pharmacokinetics andpharmacodynamics characteristics after DA ZHUI acupointinjection, contrasted to intramuscular injection, to the healthy rabbitsand febrifacient ones induced by endotoxin, moreover study the PK-PD Modelto try to explain the mechanism of the drug playing effect after acupointinjection. Methods:The experiment was divided into three parts and thefirst part was to study the pharmacokinetics after acupoint injection tothe healthy rabbits. Sixteen health rabbits were randomly divided intotwo groups(group A and B), one half for acupoint injection, and the othersfor i.m by means of the same single dosage(20mg/kg), got the bloodaccording to the time-points, detected the plasma concentration in theHPLC, and handled the concentration-time data with the SPSS and DAS PKsoftware. The second part experiment had three groups, and the firstgroup(groupâ… ) were injected E. coli endotoxin (20EU/kg)in the edge ofoto-vein to cause a febrifacient model and recorded the rabbits'temperature by time-points;The other two group also were injected E. coliendotoxin (20EU/kg) in the edge of oto-vein to cause a febrifacientmodel, and then one group(groupâ…¡) were treated with 21mg/kg paracetamolinjected in DA ZHUI acupoint, meanwhile, groupâ…¢were treated with 42mg/kgparacetamol with intramuscular injection, and both groups were recordedthe temperature. The third part was to use the plasm concentration andtemperature records of groupâ…¡andâ…¢to model the PK-PD model with thehelp of WinNonlin 5.0.1 software. Results: The first part experiment'concentration-time curve were all fitted a two-compartment Model withist Order Absorption(weight=1/C²).The groupA' s main pharmacokinetic parameters were as follows: C_max=23.1880±2.4785(mg/L), T_peak=0.5000±0.0000(h),T_1/2Ka=0.3821±0.1086(h), T_1/2α=2.1260±0.9838(h), T_1/2β=10.1621±4.0967(h), AUC_0～12h=34.5331±4.1815(mg/L. h), Ka=3.7364±1.2723(h^-1),MRT_0～12h=1.3159±0.0581(h);The groupB' s main pharmacokinetic parameterswere as follows: C_max=10.3807±1.1172(mg/L), T_peak=0.7188±0.0566(h),T_1/2Ka=0.4052±0.0852(h), T_1/2α=0.7986±0.0919(h), T_1/2β=3.0048±0.6897 (h), AUC_0～12h=28. 4241±2.8119(mg/L. h), Ka=2.9775±1.1453 (h^-1), MRT_0～12h=2.1684±0.1053(h). The secod part experiment' s concentration -timecurve were all fitted a two-compartment Model with 1st OrderAbsorption(weight=1/C²). The groupâ…¡' s main pharmacokinetic parameterswere as follows: C_max=28.3642±6.2362 (mg/L), T_peak=0.5625±0.0784 (h),T_1/2Ka=0.3681±0.1438 (h), T_1/2α=5.3741±2.0281 (h), T_1/2β=0.8689±0.1306(h), AUC_0～12h=33.0128±5.3235 (mg/L. h), Ka=4.3066±3.5287 (h^-1), MRT_0～12h=1.6846±0.1791 (h); The groupâ…¢' s main pharmacokinetic parameterswere as follows: C_max=22.5670±3.8269 (mg/L), T_peak=0.7750±0.0692 (h),T_1/2Ka=0.8672±0.2252 (h), T_1/2α=3.3696±0.7568 (h), T_1/2β=1.2975±0.2412(h), AUC_0～12h=57.7820±9.0330 (mg/L. h), Ka=1.9504±0.7449 (h^-1), MRT(0～12h)=2.9679±0.2036 (h). The third part experiment we modeled the PK-PDmodel of groupâ…¡andâ…¢, and the paracetamol with 21mg/kg acupointinjection and 42mg/kg intramuscular injection all had the same E-C_p Curvewith a un time hysteretic ring, and the pharmacodynamics model were fitteda Sigmolid- Emax model supposed one effect chamber. The groupâ…¡' s mainPK-PD parameters were as follow: E_max=0.981±0.155 (℃), ECe₅₀=0.017±0.014(mg/L), Ke0×10^-2=0.163±0.153(1/h);The groupâ…¢' s main PK-PD parameterswere as follow: E_max=1.044±0.226 (℃), ECe₅₀=0.171±0.485 (mg/L), Ke0×10^-2=1.084±3.0820.15 (1/h). Conclusion:â‘ Contrasted to intramuscularinjection, the paracetamol that was injected in DAZHUI acupiont had theT_peak 15min ahead of schedule, got the C_max 2.234 times more thani.m. injection, could maintain the effective plasm concentration any longer, and took the drug more extensively distributed in the body.â‘¡Theparacetamol that was injected in DA ZHUI acupoint in the dosage of 21mg/kghad the same effect to cure febrifacient disease as intramuscularinjection in the dosage of 42mg/kg. At the same time, considering thepharmacokinetics parameter and plasm concentration, we drew a conclusionthat acupoint injection shows the specificity of the acupoint areas,high performance of acupoint injection' s pharmacodynamic and thedependability of acupoint and drug effect.â‘¢In the base of part two, wesuccessfully modeled the PK-PD model of acupoint and intramuscularinjection, the two group had the same E-C_p Curve with a un time hystereticring, and the pharmacodynamics model were fitted a Sigmolid-Emax modelsupposed one effect chamber, and the referred pharmacodynamics parametersshow the characters of treating the rabbits' febrifacient disease withacupoint injection and intramuscular injection and give an reference toclinical medication.