Preliminary Analysis Of The Pharmacokinetics And Transcriptome Of Macleaya Cordata Extract In Pigs

Macleaya cordata extract（containing 40%of sanguinarine（SA）,20%of chelerythrine（CHE）,40%of sulfate）,which has antibacterial,anti-inflammatory and growth promoting effects.In order to study the pharmacokinetics of Macleaya cordata extract（MCE）for its clinical application and explore its growth promoting mechanism,pigs were administered MCE by single oral,single intramuscular and multiple oral administration at a dose of 0.25mg·kg^-1.The blood samples at different times were collected and analyzed by high performance liquid chromatography-tandem mass spectrometry（HPLC-MS/MS）.The results showed that SA and CHE were rapidly metabolized into dihydrosanguinarine（DHSA）and dihydrochelerythrine（DHCHE）in pigs,respectively.After single intramuscular admini-stration,the peak concentrations(C_max)of SA and CHE were 30.16±5.85 and 69.79±15.41within 0.25,0.42±0.13 h(T_max),respectively.After 16 h,both of them were completely eliminated from the blood.After single oral administration,SA and CHE reached C_max3.40±0.36 and 5.04±1.00 ng·ml^-1at 2.75±0.27 h and 1.83±0.26 h,respectively,and their half-life(t_1/2)were 2.33±0.11 and 2.03±0.26 h,respectively.After multiple oral administration,the average steady-state concentrations(C_ss)of SA and CHE were 3.03±0.39 and 2.51±0.40 ng·m L^-1,respectively.It showed that SA and CHE were absorbed and metabolized rapidly after oral administration,and it suggested that long-term and multiple oral administrations of MCE were necessary to maintain effective plasma concentration.On the basis of previous pharmacokinetic work,pigs were fed with MCE at the recommended clinical dose(1.875 mg·kg^-1feed)as the low-dose group and 5 times recommended clinical dose(9.375 mg·kg^-1feed)as the high-dose group for 30 days.Growth performance was recorded and liver samples were collected to perform transcriptome study.The results showed that the ratio of meat to feed decreased in each dose group.And 133differentially expressed genes were up-regulated and 89 genes were down-regulated in the high-dose group.There were 158 genes up-regulated and 106 genes down-regulated in the low-dose group.Compared with the high-dose,63 genes were up-regulated and 46 genes were down-regulated in the low-dose groups.GO enrichment analysis indicated that the differentially expressed genes mainly related to steroid biosynthesis,peptidase regulatory activity and arginine metabolism.KEGG enrichment analysis indicated that the differentially expressed genes mainly involved in cell adhesion molecules,protein and fat digestion and absorption,insulin signaling pathway and glucagon signaling pathway,etc..q RT-PCR was used to verify the 8 major differentially expressed genes（PLCB4,SLC7A8,ITGB3,DMGDH,APOA4,CKB,LIPG,NPC1L1）,and the results were mainly consistent with that of transcriptome.The MCE could up-regulate the expression of key genes of SOCS2,AMPK,PLCB4,ITGB3 and SLC7A8,which resulted in regulating the metabolic changes in pigs,and improving animal immunity,glucose metabolism and other functions.In conclusion,this study on the pharmacokinetic behavior of MCE and its metabolites after different administration routes in pig provided basis for its clinical use.Through transcriptome analysis of MCE effect of promoting pig growth,the related key pathways were found and basic data was accumulated for further study on its action mechanism.