Basic Research On The Optimum Technology Of Euodiae Fructus Processed With Glycyrrhizae Radix Et Rhizoma

Objective:The pharmacokinetics of dehydroevodiamine was studied in rats by comparing Euodiae Fructus processed with different proportions of Glycyrrhizae Radix et Rhizoma and dehydroevodiamine combined with different proportions of glycyrrhetic acid to provide the experimental basis for the optimum technology of Euodiae Fructus processed with Glycyrrhizae Radix et Rhizoma and lay the foundation for further research on the processing principle of Euodiae Fructus processed with Glycyrrhizae Radix et Rhizoma.Methods:Euodiae Fructus(raw product and processed products with 100:3,100:6,100:12,100:24 Glycyrrhizae Radix et Rhizoma)was extracted with 80%ethanol.The contents of dehydroevodiamine,glycyrrhetic acid and glycyrrhetinic acid were determined by HPLC method.The drug-containing plasma samples taked from rats "orbital venous plexus were prepared by centrifuging after gavage administration.The drug-containing plasma samples were prepared by extracting with ethyl acetate.The contents of dehydroevodiamine in plasma samples were determined by UPLC method.Pharmacokinetic parameters were calculated and analyzed by PK Solutions 2.0 and SPSS 21.Results:Result of pharmacokinetics of dehydroevodiamine alone:At 15 mg-kg-1 of dehydroevodiamine,the values of AUC(0-12h)(?g-min·mL-1),AUC(0-?)(?g-min·mL-1),Cmax(?g·mL-1),Tmax(min),Vd(L·kg-1),T1/2(min)and CL(L min-1· kg-1)are 54.49 ±11.56,54.81 ±11.64,0.27 ± 0.08,52.00 ± 27.75,37.51 ± 9.56,91.52 ± 10.05 and 0.28 ± 0.05,respectively,as well as their values are 355.40 ± 106.65(P<0.01),368.68 ± 113.13(P<0.01),0.93 ± 0.25(P<0.01),216.00 ± 53.67(P<0.01),29.19 ± 6.57,117.91 ± 16.50(P<0.05)and 0.17 ± 0.05(P<0.05),respectively,at 60 mg·kg-1.Result of pharmacokinetics of dehydroevodiamine(60 mg-kg-1)in unprocessed Euodiae Fructus:The values of AUC(0-12h)(?g-min·mL-1),AUC(0-?)(?g-min·mL-1)Cmax(?g·mL-1),Tmax(min),Vd(L·kg-1),T1/2(min)and CL(L·min · kg-1)are respective 14.45 ± 1.75(P<0.01),19.80 ± 3.93(P<0.01),0.05 ± 0.01(P<0.01),120.00 ± 36.74(P<0.05),1 587.48 ± 717.73(P<0.01),387.42 ± 244.81(P<0.05)and 3.13 ± 0.60(P<0.01).Result of pharmacokinetics of dehydroevodiamine(60 mg· kg-1)in processed Euodiae Fructus:Pharmacokinetics parameters of dehydroevodiamine are AUC(0-12h)(?g-min·mL-1)(16.46 ± 4.49,19.23 ± 6.95,14.99 ± 4.96,13.21 ± 4.91),AUC(0-?)(?g-min·mL-1)(18.44 ± 3.89,21.33 ± 7.16,17.45 ± 7.75,14.57 ± 5.01),Cmax(?g·mL-1)(0.06 ± 0.02,0.08 ±0.02(P<0.05),0.05 ± 0.02,0.05 ± 0.01),:Tmax(min)(132.00 ± 26.83,126.00 ± 32.86,156.00 ±32.86,138.00 ± 40.25),Vd(L·kg-1)(1 116.46 ± 584.61,950.32 ± 504.42,976.20 ± 393.60,1016.57 ± 782.16),T1/2(min)(218.96 ± 80.93,212.28 ± 80.82,185.94 ± 104.42(P<0.05),165.95 ± 123.48(P<0.05))and CL(L min-1·kg-1)(3.39 ± 0.80,3.03 ± 0.83,4.09 ± 1.94,4.45 ±1.24)in extracts of Euodiae Fructus processed with the 100:3,100:6,100:12 and 100:24 proportion of Glycyrrhizae Radix et Rhizoma.Result of pharmacokinetics of dehydroevodiamine(15 mg·kg-1)combined with glycyrrhetic acid:Pharmacokinetics parameters of dehydroevodiamine are AUC(0-12h)(?g-min·mL-1)(45.43 ± 15.92,59.46 ± 12.44,62.49 ± 14.51,60.20 ± 15.75),AUC(0-?)(?g-min·mL-1)(46.83 ± 14.87,59.63 ± 12.46,63.13 ± 14.72,60.86 ± 15.29),Cmax(?g ·mL-1)(0.25 ± 0.08,0.32± 0.07,0.30 ± 0.09,0.29 ± 0.101),Tmax(min)(72.00 ± 26.83,72.00 ± 34.21,72.00 ± 26.83,102 ± 26.83(P<0.05)),Vd(L·kg-1)(91.08 ± 67.57(P<0.05),29.44 ± 13.01,36.27 ± 7.18,40.71 ± 22.63),T1/2(min)(164.14 ± 78.58(P<0.05),76.44 ± 25.79,102.07±8.33,103.14 ±37.89)and CL(L min-1 ·kg-1)(0.35 ± 0.11,0.26 ± 0.07,0.25 ± 0.05,0.26 ±0.06)in dehydroevodiamine combined with the 20:1,10:1,5:1 and 5:2 proportion of glycyrrhetic acid.Conclusions:Dehydroevodiamine monomer is easier to absorb in rats and eliminate slowly.Some components of the extracts of Euodiae Fructus can reduce the absorption of dehydroevodiamine in rats,and accelerate its elimination.Euodiae Fructus processed with Glycyrrhizae Radix et Rhizoma can increase the absorption of dehydroevodiamine in rats,and increase the peak of blood concentration,shorten its half-life,especially Euodiae Fructus processed with Glycyrrhizae Radix et Rhizoma(100:6).Glycyrrhetic acid does not change the pharmacokinetic process of dehydroevodiamine in rats significantly.