Pharmacokinetic Characterization and Bioavailability Barrier for the Key Active Components of Botanical Drug Antitumor B (ATB) in Mice for Chemoprevention of Oral Cancer.
Pharmacokinetic Characterization and Bioavailability Barrier for the Key Active Components of Botanical Drug Antitumor B (ATB) in Mice for Chemoprevention of Oral Cancer.
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植物药抗肿瘤B(ATB)主要活性成分在小鼠体内的药代动力学特征及生物利用度研究
DOI：
10.1021/acs.jnatprod.1c00501
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发表时间：
2021-09-24
影响因子：
5.1
通讯作者：
Hu, Ming
中科院分区：
文献类型：
--
作者：
Bui, Dinh;Yin, Taijun;Duan, Shengnan;Wei, Bo;Yang, Peiying;Wong, Stuart J.;You, Ming;Singh, Rashim;Hu, Ming
本研究的目的是研究口腔癌化学预防药物抗肿瘤B(ATB)的主要活性成分(KAC)的药代动力学特征，确定其重要的生物利用度障碍和药理途径。KAC(苦参碱、独断胺、秦皮酮和马奎因)通过口腔鳞癌细胞(SCC-9、CAL-27)的抗增殖试验和内毒素诱导的SCC-9细胞的抗炎(抗COX2)试验得到证实，这与用计算机网络药理学方法预测的结果一致。静注后测定KAC的药代动力学和生物利用度。小鼠(n=5)灌胃给予ATB(500 mg/kg)、腹腔注射(500 mg/kg)和灌胃(100、500、4000 mg/kg ATB和5 mg/kg单剂KAC)。KAC的口服生物利用度分别为9.0±3.3%、4.6±2.8%、3.9±1.9%和0.2±0.1%(苦参碱、马钱子碱、独特明和秦皮酮)。口服KAC的生物利用度低主要是由于KAC在肝脏(对所有KAC)和肠道(仅对苦参碱和秦皮酮)的首过代谢，因为KAC具有良好的溶解性和渗透性。口服后的多剂量PK研究显示，七次剂量后，独断胺和马卡因在血液中的蓄积分别为23.2和8.5倍，而其他KAC没有显示出可测量的蓄积。此外，唾液中苦参碱的水平高于他们的血浆水平，这表明它们优先分布到目标作用部位。综上所述，ATB确认的KAC的系统生物利用度较低，但在反复给药后唾液中发现了高水平的独断胺和苦参碱，这表明探索利用局部给药系统在口腔癌化学预防中取得更好的效果可能是有成效的。此外，在化学预防试验期间，唾液中显著浓度的独断胺和苦参碱可能被用作药物监测工具，以跟踪患者的依从性。
The purpose of the present study was to characterize the pharmacokinetics profiles and identify important bioavailability barriers and pharmacological pathways of the key active components (KACs) of Antitumor B (ATB), a promising chemopreventive agent against oral cancer. KACs (matrine, dictamine, fraxinellone, and maackiain) were confirmed using an antiproliferative assay in oral squamous cancer cells (SCC-9, Cal-27) and an anti-inflammatory (anti-COX2) assay using LPS-induced SCC-9 cells, consistent with those predicted using an in silico network pharmacology approach. Pharmacokinetics and bioavailabilities of KACs were determined after i.v. (500 mg/kg ATB), i.p (500 mg/kg ATB), and oral administration (100, 500, 4000 mg/kg ATB and 5 mg/kg individual KACs) in mice (n = 5). The oral bioavailability values of KACs (500 mg/Kg ATB dose) were 9.0 ± 3.3%, 4.6 ± 2.8%, 3.9 ± 1.9%, and 0.2 ± 0.1% for matrine, maackiain, dictamine, and fraxinellone, respectively. The low bioavailability of orally administered KACs was mostly due to first-pass metabolism in the liver (for all KACs) and intestine (for only matrine and fraxinellone) because KACs have good solubilities and permeabilities. Multiple-dose PK studies following oral administration showed 23.2 and 8.5 fold accumulation of dictamine and maackiain in blood, respectively, after seven doses, whereas other KACs did not display measurable accumulation. Also, saliva levels of matrine were higher than their plasma levels, suggesting their preferential distribution to the targeted site of action. In conclusion, the systemic bioavailabilities of confirmed KACs of ATB were low but high levels of dictamine and matrine were found in saliva after repeated drug administration, which suggests that it may be fruitful to explore the use of local drug delivery system to achieve better efficacy in oral cancer chemoprevention. Moreover, significant concentrations of dictamine and matrine in saliva may be used as a drug-monitoring tool to track patient compliance during chemoprevention trials.
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DOI：
10.1002/hed.1049
发表时间：
2001-05-01
影响因子：
2.9
作者：
Epstein, JB;Robertson, M;Stevenson-Moore, P
通讯作者：
Stevenson-Moore, P
影响因子：
3.7
作者：
Lailulo Y;Kitenge M;Jaffer S;Aluko O;Nyasulu PS
通讯作者：
Nyasulu PS
影响因子：
3.9
作者：
Gao, Guanghua;Law, Francis C. P.
通讯作者：
Law, Francis C. P.
影响因子：
5.2
作者：
Nasry WHS;Rodriguez-Lecompte JC;Martin CK
通讯作者：
Martin CK
DOI：
10.1002/hed.10015
发表时间：
2002-02-01
影响因子：
2.9
作者：
Friedlander, P;Caruana, S;Shah, JP
通讯作者：
Shah, JP