Study On Absorption Mechanism And Pharmacokinetics Of Isochlorogenic Acid A In Rats

Objective: To study the absorption mechanism and pharmacokinetics of isochlorogenicacid A.Method: The in vitro everted rats gut sac model and in situ single-pass intestinal perfusionmodel were used to explore the intestinal absorption character of isochlorogenic acid A indifferent intestinal segments (duodenum, jejunum, ileum and colon), and the difference onthose the two model on research isochlorogenic acid A intestinal absorption was compared.Rats were administered isochlorogenic acid A intravenously (i.v.)(16,32,64mg·kg-1) ororally (90mg·kg-1). The plasma concentration of isochlorogenic acid A was taken forHPLC analysis. Pharmacokinetic parameters were calculated using the3P97software(Chinese Society of Mathematical Pharmacology). The absolute bioavailability (Fabs%) wascalculated. The software SPSS was used to evaluate correction of the intestinal absorptionrate (Fl%) of isochlorogenic acid A, which was got by using the in situ single-passintestinal perfusion, and the absorption rate (Fa%) of isochlorogenic acid A, which was gotby using the animal model. The linearity regression was determined by plotting Fa%to Fl%.The first-pass of isochlorogenic acid A was studied by in situ once-through vascularlyperfused rat intestinal preparation and in situ once-through perfused rat live preparation.Isochlorogenic acid A (60.98or84.63μg·mL-1) was delivered into the intestine via thesuperior mesenteric artery to investigate the intestine first-pass effect on isochlorogenic acid A. Isochlorogenic acid A (5.39,12.2μg·mL-1) was delivered into the live via the portalvein to investigate the live first-pass effect on isochlorogenic acid A.Result: Using the in vitro everted rats gut sac model, there were findings that the differentconcentration of isochlorogenic acid A in the intestinal segments absorption was linearity;the Ka of isochlorogenic acid A increased along with the raised dosage (P<0.05), and theKa in the ileum obviously higher than that in the duodenum, jejunum and colon, namely theileum was the best absorption section. The absorption of isochlorogenic acid A was nosaturated in high concentration. Applying the in situ single-pass intestinal perfusion model,there were findings that there was upgrade tendency between the Peff of duodenum,jejunum, ileum and colon in different concentration of isochlorogenic acid A, and it hasobvious difference among each concentration. The Peff in the ileum obviously higher thanthat in the duodenum, jejunum and colon, namely the ileum was the best absorption section.Following intravenous dosing, the t1/2of isochlorogenic acid A were29min and the AUCof isochlorogenic acid A increased along with the raised dosage, indicating thepharmacokinetics of isochlorogenic acid A was linear behavior. The absolute bioavailabilityof isochlorogenic acid A in rat was found to be30.71%. The correlation coefficient was0.974between Fa%and Fl%, and was positively correlated, and the linear equation wasFl%=0.523Fa%+3.715. When isochlorogenic acid A concentration at60.98and84.63μg·mL-1, the intestinal extraction ratios (El%) were45.94%and52.37%, respectively. Withisochlorogenic acid A concentration at5.39and12.2μg·mL-1, the hepatic extraction ratios(Eh%) were48.01%and54.47%, respectively.Conclusion: The transport mechanisms of isochlorogenic acid A was passive diffusion, andhad a special absorption window. Isochlorogenic acid A was a short time half timemedicine and shown to have low oral bioavailability in rats. The pharmacokinetics ofisochlorogenic acid A was linear kinetics. By the correlative evaluation of Fl%and Fa%, thein situ single-pass intestinal was high reliability on prediction isochlorogenic acid Aabsorption. Isochlorogenic acid A was high first-pass effect.