TY - JOUR
T1 - Pharmacokinetic Characterization and Bioavailability Barrier for the Key Active Components of Botanical Drug Antitumor B (ATB) in Mice for Chemoprevention of Oral Cancer
AU - Bui, Dinh
AU - Yin, Taijun
AU - Duan, Shengnan
AU - Wei, Bo
AU - Yang, Peiying
AU - Wong, Stuart J.
AU - You, Ming
AU - Singh, Rashim
AU - Hu, Ming
N1 - Funding Information:
This project is supported by the NIH Grants CA205633 and GM070737
Publisher Copyright:
© 2021 American Chemical Society and American Society of Pharmacognosy
PY - 2021/9/24
Y1 - 2021/9/24
N2 - 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 observedin vitroactivities of KACs were consistent with their cell signaling pathways predicted using thein siliconetwork 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.
AB - 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 observedin vitroactivities of KACs were consistent with their cell signaling pathways predicted using thein siliconetwork 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.
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U2 - 10.1021/acs.jnatprod.1c00501
DO - 10.1021/acs.jnatprod.1c00501
M3 - Article
C2 - 34463097
AN - SCOPUS:85114898525
SN - 0163-3864
VL - 84
SP - 2486
EP - 2495
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 9
ER -