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