Determination And Pharmacokinetic Study Of Main Ingredients In Radix Aucklandiae

Radix Aucklandiae (RA) is the dried root of Aucklandia lappaDecen.. It has been widely used in traditional Chinese medicine fortreatment of idiopathic edema, functional abdominal pain in children,peptic ulcer, chronic gastritis and coronary heart disease.Pharmacological studies have demonstrated that it exhibited promotinggastrointestinal movement, anti-ulcer and contracting gallbladder effects.In order to quality control RA and preparations including RA, and tofurther explain metabolic profiling and metabolic pathways of RA in vivo,costunolide and dehydrocostuslactone, main ingredient in RA, weredetermined in RA and Xin-Ke-Shu preparations, and developed analyticalmethods for quality control of RA. The pharmacokinetics of activeingredients costunolide and dehydrocostuslactone in RA were studied, itrevealed metabolic profiling in vivo of RA in the normal and gastric ulcerrats. The metabolites of costunolide and dehydrocostuslactone wereidentified, it investigated metabolic pathways in vivo of RA in rats.A quantitative method using HPLC for simultaneous determination of costunolide and dehydrocostuslactone in RA and Xin-Ke-Shupreparations was established. Quality control of13batches ofXin-Ke-Shu preparations purchased from7manufacturers wereinvestigated, the results showed that the content of dehydrocostuslactonewas always higher than that of costunolide, however, the obviousdifference of the content of costunolide and dehydrocostuslactone wasobserved in some batches, even up to8times. And even different batchesof the same manufacturers also appear the phenomenon mentioned above.This variation might be due to the difference of quality of RA andproduction processs. Therefore, in the Xin-Ke-Shu preparation productionprocess, we should pay attention for quality control of RA.Costunolide and dehydrocostuslactone were the main activeingredients in RA. A LC-MS/MS method was built up for accuratequantitative analysis of costunolide and dehydrocostuslactone in normalrat serum. The paper monitored the plasma concentration of costunolideand dehydrocostuslactone after oral administration of costunolide (84.4mg/kg) and dehydrocostuslactone (103.7mg/kg). Pharmacokinetics wasanalyzed using the non-compartmental model by the software-WinNonlin6.1, the results showed the bimodal phenomenon appeared in theconcentration-time curve of costunolide and dehydrocostuslactone, whichmanifested that metabolism of costunolide and dehydrocostuslactone mayexperience enterohepatic circulation. The first peak all occurred at less than45min, it showed these two compounds were absorbed fast in vivo.In order to investigate the influence of the complex ingredient in RA forsingle compound in vivo, the paper monitored the plasma concentration ofcostunolide and dehydrocostuslactone after oral administration of RAextract (650mg/kg, equivalent to84.4mg/kg of costunolide and103.7mg/kg of dehydrocostuslactone) and the mixture of costunolide (84.4mg/kg) and dehydrocostuslactone (103.7mg/kg). The results showed thatthere were a little influence beteen costunolide and dehydrocostuslactone,however, certain compounds in RA extract promoted the absorption ofcostunolide and dehydrocostuslactone, reduced the clearance of them andextended the efficacy.Pharmacokinetics influence of costunolide and dehydrocostuslactoneafter oral administration of RA extract (650mg/kg) in gastric ulcer ratswere studied. The bimodal phenomenon appeared in theconcentration-time curve of costunolide and dehydrocostuslactone, whichmanifested that metabolism of costunolide and dehydrocostuslactone mayalso experience enterohepatic circulation in gastric ulcer rats. Comparedwith pharmacokinetics of costunolide and dehydrocostuslactone after oraladministration of RA extract in normal rats, the first peak concentrationof costunolide in gastric ulcer rats decreased by30%, the second peaktime extended1time, the total clearance rate reduced by63%. The firstpeak concentration of dehydrocostuslactone in gastric ulcer rats decreased by68%, the second peak time extended2time, the total clearance ratereduced by37%. It indicated that the gastric damage affects theabsorption of the drug, which resulted in the reduction of the peakconcentration and extension of the peak time, and affected the eliminationof drug.A UPLC/Q-TOF MSEsystem was applied for preliminary study ofmetabolites in normal rats after oral administration of costunolide anddehydrocostuslactone, respectively. The data were processed by analysissoftware Masslynx4.1, and the results showed that the number ofmetabolites of costunolide and dehydrocostuslactone were9and7,respectively. The type of metabolic pathways in vivo involved reduction,hydration, glycine conjugation, sulfate conjugation, methylation andacetylation reaction.