Pharmacokinetic Characterization and Bioavailability Barrier for the Key Active Components of Botanical Drug Antitumor B (ATB) in Mice for Chemoprevention of Oral Cancer,Journal of Natural Products

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Pharmacokinetic Characterization and Bioavailability Barrier for the Key Active Components of Botanical Drug Antitumor B (ATB) in Mice for Chemoprevention of Oral Cancer
Journal of Natural Products ( IF 3.3 ) Pub Date : 2021-08-31 , DOI: 10.1021/acs.jnatprod.1c00501
Dinh Bui ₁ , Taijun Yin ₁ , Shengnan Duan ₁ , Bo Wei ₂ , Peiying Yang ₂ , Stuart J Wong ₃ , Ming You ₄ , Rashim Singh ₁ , Ming Hu ₁

Affiliation

This study aims to characterize the pharmacokinetic (PK) profiles and identify important bioavailability barriers and pharmacological pathways of the key active components (KACs) of Antitumor B (ATB), a chemopreventive agent. KACs (matrine, dictamine, fraxinellone, and maackiain) of ATB were confirmed using the antiproliferative assay and COX-2 inhibition activities in oral cancer cells. The observed in vitro activities of KACs were consistent with their cell signaling pathways predicted using the in silico network pharmacology approach. The pharmacokinetics of KACs were determined after i.v., i.p., and p.o. delivery using ATB extract and a mixture of four KACs in mice. Despite good solubilities and permeabilities, poor oral bioavailabilities were estimated for all KACs, mostly because of first-pass metabolism in the liver (for all KACs) and intestines (for matrine and fraxinellone). Multiple-dose PK studies showed 23.2-fold and 8.5-fold accumulation of dictamine and maackiain in the blood, respectively. Moreover, saliva levels of dictamine and matrine were found significantly higher than their blood levels. In conclusion, the systemic bioavailabilities of ATB-KACs were low, but significant levels of dictamine and matrine were found in saliva upon repeated oral administration. Significant salivary concentrations of matrine justified its possible use as a drug-monitoring tool to track patient compliance during chemoprevention trials.

中文翻译：

植物药抗肿瘤 B (ATB) 关键活性成分在小鼠体内化学预防口腔癌的药代动力学特征和生物利用度障碍

本研究旨在表征化学预防剂抗肿瘤 B (ATB) 的药代动力学 (PK) 特征，并确定其关键活性成分 (KAC) 的重要生物利用度障碍和药理学途径。通过口腔癌细胞中的抗增殖测定和 COX-2 抑制活性，证实了 ATB 的 KAC（苦参碱、白客明、fraxinellone 和 maackiain）。观察到的 KAC体外活性与其使用计算机网络药理学方法预测的细胞信号传导途径一致。使用 ATB 提取物和四种 KAC 的混合物在小鼠体内进行 iv、ip 和 po 递送后测定 KAC 的药代动力学。尽管溶解度和渗透性良好，但所有 KAC 的口服生物利用度估计都很差，这主要是因为肝脏（所有 KAC）和肠道（苦参碱和 fraxinellone）的首过代谢。多剂量 PK 研究显示，白术胺和 maackiain 在血液中的积累分别是 23.2 倍和 8.5 倍。此外，唾液中白术胺和苦参碱的含量显着高于血液中的含量。总之，ATB-KACs 的全身生物利用度较低，但重复口服给药后，唾液中发现显着水平的白术胺和苦参碱。苦参碱在唾液中的显着浓度证明其可以用作药物监测工具，以在化学预防试验期间跟踪患者的依从性。

更新日期：2021-09-24

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