Zhao Chengcheng, Ying Zheming, Hao Dong, Zhang Wenjie, Ying Xixiang, Yang Guanlin
School of Pharmacy, Liaoning University of Traditional Chinese Medicine, 116600, Dalian, China.
School of the First Clinic, Liaoning University of Traditional Chinese Medicine, 110032, Shenyang, China.
Biopharm Drug Dispos. 2019 Apr;40(3-4):112-120. doi: 10.1002/bdd.2175. Epub 2019 Mar 11.
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 (AUC ) 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 AUC 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.
马齿苋酰胺A（OA）是从马齿苋中分离出的一种新生物碱，在我们之前的研究中已证明其经大鼠口服给药后生物利用度较低（F）。因此，为阐明其生物利用度低的原因，建立了肝脏、胃和肠道首过效应模型，并验证了一种快速、灵敏的超高效液相色谱法（UHPLC），用于经股静脉、门静脉、胃和肠道途径给药后的测定。选择低剂量和高剂量组的维拉帕米、咪达唑仑和冰片作为细胞色素P450 3A亚家族（CYP3A）和P-糖蛋白（P-gp）的抑制剂，以提高马齿苋酰胺A的低生物利用度。此外，还采用了直肠给药方法来提高马齿苋酰胺A的生物利用度。结果表明，马齿苋酰胺A经肝脏、胃和肠道途径给药的生物利用度分别为92.16%、84.88%和5.76%。给予10和30 mg/kg维拉帕米后，从零至无穷大的血浆浓度-时间曲线下面积（AUC）略有增加（p>0.05），但给予0.4和1.2 mg/kg咪达唑仑以及8和24 mg/kg冰片后显著增加（p<0.05）。此外，直肠低位和高位给药后的AUC值分别与静脉注射和门静脉注射相似。我们的研究表明，肠道首过效应是导致马齿苋酰胺A在大鼠体内生物利用度低的主要原因，这是由于它是CYP3A和P-gp的底物以及肠道吸收较差。
