吴茱萸经不同比例甘草炮制后对去氢吴茱萸碱药动学的影响

Effect of Euodiae Fructus Processed with the Different Proportions of Glycyrrhizae Radix et Rhizoma on the Pharmacokinetics of Dehydroevodiamine in Rats

目的通过比较吴茱萸生品和不同比例甘草制品中去氢吴茱萸碱在大鼠体内的药动学变化,揭示吴茱萸甘草炮制的科学内涵。方法吴茱萸甘草制品按2015年版《中国药典》制吴茱萸项下方法进行制备;采用超高效液相色谱(UPLC)分析大鼠血浆中去氢吴茱萸碱的质量浓度;采用PK Solutions 2.0按非房室模型模拟血药浓度-时间曲线及药动学参数。结果去氢吴茱萸碱的给药剂量从15 mg·kg^(-1)增加到60 mg·kg^(-1),AUC和Cmax显著增加(P<0.05或P<0.01),浓度为60 mg·kg^(-1)时,Tmax显著延长(P<0.01);当以15 mg·kg^(-1)的剂量做参照,给予30 mg·kg^(-1)和60 mg·kg^(-1)剂量去氢吴茱萸碱会有近似的相对生物利用度,分别为153.72%和168.16%;灌胃给予去氢吴茱萸碱浓度为60 mg·kg^(-1)的吴茱萸生品或不同比例甘草制品醇提物后,与同剂量的去氢吴茱萸碱单体相比,AUC和Cmax显著降低(P<0.001),生物利用度仅有3.95%~5.78%;与吴茱萸生品相比,仅100∶6比例甘草制品中去氢吴茱萸碱的Cmax增加(P<0.05),生物利用度提高。结论在吴茱萸生品醇提物中去氢吴茱萸碱的Cmax和生物利用度均较低,采用100∶6的甘草炮制后可以提高去氢吴茱萸碱的Cmax和生物利用度。

Objective The scientific connotation of EF processed with Glycyrrhizae Radiyrt Rhizoma(Gly)was revealed by comparing the difference of the pharmacokinetics of dehydroevodiamine(DHE)in rats after gavage administation of the unprocessed product of Euodiae Fructus(EF)(UEF)and the products of EF processed with the different proportions of Gly(GEFs).Methods The GEFs were prepared according to the processing method of EF in Chinese Pharmacopoeia(2015 edition).The contents of DHE in rat blood samples were analyzed using Ultra-high performance liquid chromatography(UPLC)assay.Concentration-time profiles and pharmacokinetic parameters were determined by the standard non-compartmental method and calculated with PK Solutions 2.0.Results Area under curve(AUC)and Peak concentration(Cmax)of DHE was significant increased(P<0.05或P<0.01)when the dosage of alone DHE was increased from 15 mg·kg^(-1)to 60 mg·kg^(-1),and Tmax was dramatically raised(P<0.01)at 60 mg·kg^(-1).There was similar bioavailability(F)(153.72%and 168.16%)between 30 and 60 mg·kg^(-1)versus 15 mg·kg^(-1).After oral administration of the ethanol exacts of UEF or GEFs containing 60 mg·kg^(-1)of DHE,their AUC and Cmax were markedly decreased(P<0.001)compared with alone DHE at the same dosage,and the bioavailabilities of DHE in the exacts of UEF and GEFs were only from 3.95%to 5.78%.Compared with UEF,Cmax and F of DHE were increased(P<0.05)in GEF/100:6.Conclusion The Cmax and F of DHE in the ethanol exacts of UEF was significantly reduced,and the Cmax and F of DHE were increased after EF processed with 100:6 proportions of Gly.