Based On The Modulation Of Intestinal UGT Metabolism By Cajaninstilbene Acid Loaded Self-Microemulsion And Its Bioavailability Evaluation

Oral ingestion of a drug is the clinically preferred mode of administration,which is more easily accepted by patients because of its simplicity and safety.The enzymes associated with the first-pass effect are abundant in the liver and intestine,and uridine diphosphate glucose transferase(UGT)is one of them.The enzyme degrades natural phenolic drugs,and catalyzes the glucuronidation reaction of the drug,producing inactive metabolites that reduce the concentration absorbed into the blood,resulting in extremely low bioavailability.Cajaninstilbene acid(CSA)is a naturally occurring phenolic compound that has ademonstrates various types of pharmacological activities due to its antioxidant properties.However,the applications of CSA are significantly limited by its exceedingly low oral bioavailability.One of the main causes of poor bioavailability refers to the first-pass glucuronidation in the liver and intestine.Therefore,inhibiting the UGT metabolism can be an effictive approach to improve the bioavailabilty and efficacy of CSA.This study established a high performance liquid chromatography(HPLC)method for the determination of CSA content,and a comprehensive methodological verification of CSA in vivo and in vitro detection methods.The SME-1 of inhibiting UGT activity was prepared:oil phase Labrafil,emulsifier RH40/Labrasol,co-emulsifier PEG400(w/w/w=2:6:2),the SME-2 of without inhibition of UGT activity:oil phase soybean oil,emulsifier OP-10,co-emulsifier glycerol(w/w/w=1:4.5:4.5).These two preparations were subsequently characterized by particle size,potential,and in vitro drug release.The UGT inhibition mechanisms of SME were explored using Caco-2 cells experiments on SME-1 and SME-2.The effects of SME-1 and SME-2 on the absorption and transport of CSA in the intestine were investigated by vitro intestinal valgus test.Finally,SME-1,SME-2 and CSA were orally administered to rats,and plasma concentrations of CSA and CSA-G were detected by HPLC nalysis.The effect of SME-1on pharmacokinetic properties of CSA as explored by compareing the pharmacokinetic parameters in each group.Results showed:the in vivo and in vitro HPLC methodological inspections of CSA met the requirements.The drug loading of both SME-1 and SME-2 were 40 mg/g.SME-1 were 25.69 nm around in particle size with potential of-8.06 mV and SME-2 were 22.45 nm around in particle size with potential of-10.46 mV.Drug release from SME-1 and SME-2 was reached 48.58%and 55.23%at 12 h.Both SME-1 and SME-2 were active transport.The uptake of SME-1 by cells was significant higher;the Caco-2 cell transport assay showed a significant increase in SME-1 transport rate compared with SME-2.The vitro transport experiment using rat everted gut sacs showed,in the 120 min,that the CSA transport percentage in the SME-1 group reached 7.79%,while the SME-2 and free drug groups only reached 1.17%and 0.7%.SME-1 was able to greatly enhance oral bioavailability of CSA.Comepared with SME-2,SME-1 increased from 35.40%to 57.26%in systemic exposure of CSA,SME-1 caused significant reductions in UGT metabolism of CSA.In summary,SME-1 successfully inhibited intestinal UGT activity,leading to the increased bioavailability of CSA.