Investigating the bioavailabilities of olerciamide A via the rat's hepatic, gastric and intestinal first-pass effect models.

Olerciamide A (OA), as a new alkaloid isolated from Portulaca oleracea L., has been proved to possess a low bioavailability (F) after oral administration in rats in our previous study. Hence, to clarify the reasons of its low bioavailability, the hepatic, gastric and intestinal first-pass effect models were established, and a rapid, sensitive UHPLC method were validated and applied for the determination after dosed via femoral, portal, gastric and intestinal routes.. Being the inhibitors of CYP3A and P-gp, verapamil, midazolam and borneol at low and high dose groups were selected to improve the low bioavailability of OA. Moreover, rectal administration method was also carried out to improve the bioavailability of OA. The results showed that the bioavailability of OA at hepatic, gastric and intestinal were 92.16%, 84.88% and 5.76%, respectively. The areas under the plasma concentration-time curve from zero to infinity (AUC0→∞ ) were a little increased after dosed at 10 and 30 mg/kg verapamil (P > 0.05), but remarkable after dosed at 0.4 and 1.2 mg/kg midazolam as well as 8 and 24 mg/kg borneol (P < 0.05). Besides, the AUC0→∞ values dosed at lower and upper rectums were separately similar to intravenous and intraportal administrations. Our study showed that the intestinal first-pass effect was mainly contribute to the low bioavailability of OA in rats due to OA being the substrates of the CYP3A and P-gp as well as its poor intestinal absorption.