Biopharmaceutical and Pharmacokinetic Studies of a Botanical Drug – Antitumor B – as a Chemopreventive Agent Against Oral Cancer

Date

2021-12-08

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Abstract

Purpose and Specific Aims Antitumor B (ATB), also known as Zeng Sheng Ping, is a Chinese herbal mixture composed of six plants and approved for use in China for dysplasia treatment. Many studies in rodents and humans have been published demonstrating the chemopreventive activity of ATB against the upper aerodigestive tract tumors as well as other types of cancer (e.g. lung, esophageal and oral carcinoma). The overall objectives of this project are to confirm the key active compounds (KACs) of ATB against oral cancer and their plausible mechanisms of action via a network pharmacology approach, characterize fully KAC’pharmacokinetic behaviors in vitro and in vivo and build appropriate PK models to describe the PK behaviors and enhance their distribution to the oral tissues via the use of an oral adhesive patch. Methods The KAC of ATB were confirmed using antiproliferation and antiinflammation assays using human oral cancer cell lines SCC-9 and Cal-27. Pharmacokinetic studies of ATB were conducted in healthy mice, rats, and adult humans to determine the pharmacokinetics and bioavailability of KACs. Phoenix NLMETM and GastroPlus® software were used to build the PK models to describe the correlation between drug concentration in human plasma & saliva and to do interspecies scaling of the drug concentration in animals and humans. The buccal delivery formulation was made by solvent casting method for local delivery of ATB to the targeted oral tissue. Results Matrine, dictamine, maackiain, and fraxinellone were confirmed as the key active compounds (KACs) based on the antiproliferation assay and PGE2 assays. A LC-MS/MS method was adapted and then validated to analyze these compounds in several biological matrixes simultaneously. Matrine and dictamine were detected in both the rodent and human plasma and saliva, suggesting their distribution to the targeted site of action. The oral bioavailability values in mice of KACs were 3.2 ± 1.8%, 4.6 ± 2.8%, 3.9 ± 1.9%, and 0.2 ± 0.1% for matrine, dictamine, maackian, and fraxinellone, respectively. Significant higher concentration of Matr in the saliva human and mouse samples suggested an active secrection of this compound to human and mouse saliva. Compartmental co-modeling strategy and PBPK models were successfully constructed to correlate the matrine concentration in plasma and saliva and to enable interspecies scaling, respectively. The buccal adhesive patch formulation efficiently delivered certain KACs to the oral tissues. Conclusion and Significance This study contributes to the pharmacokinetics of antitumor B in rodents and healthy adults. We report the first clinical evidence of significantly high secretion of certain active compounds (matrine) in a multi-component botanical (Antitumor B, ATB) into human saliva from the systemic circulation. Saliva matrine can be used as a compliance monitoring tool during upcoming clinical trials of ATB. The pharmacokinetic models were successfully constructed to correlate the matrine concentration in plasma and saliva and to enable interspecies scaling. Matrine may be used to check a patient’s compliance with ATB dosing. The buccal adhesive patch was developed, tested, and is a promising lead for localized and targeted delivery of ATB and/or its KACs.

Description

Keywords

Zeng sheng ping, PBPK modeling

Citation

Portions of this document appear in: Bui, Dinh, Li Li, Taijun Yin, Xinli Wang, Song Gao, Ming You, Rashim Singh, and Ming Hu. "Pharmacokinetic and metabolic profiling of key active components of dietary supplement Magnolia officinalis extract for prevention against oral carcinoma." Journal of agricultural and food chemistry 68, no. 24 (2020): 6576-6587; and in: Bui, Dinh, Taijun Yin, Shengnan Duan, Bo Wei, Peiying Yang, Stuart J. Wong, Ming You, Rashim Singh, and Ming Hu. "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 84, no. 9 (2021): 2486-2495.