Prediction Of Structure, Exposure, Dose About The Series Of Coumarin Compounds Based On The PBPK Model

In today’s society, more and more people are suffering from cancer due to environmental pollution, food safety, bad life habits and other factors. Cancer has become a common and serious threat to human health. Therefore, discovery and development of anti-tumor drugs has become the focus of drug research institutions.Series of coumarin compounds are natural products with strong physiological activity, pharmacological activity and biological activity. Among them, aesculetin, a natural coumarin compound, exhibits multiple biological properties including anti-tumor, anti oxidative, anti-inflammatory. However, aesculetin and its derivatives / drug candidates can be rapidly eliminated via phase II metabolizing enzymes in human. In order to improve the metabolic stability and anti-tumor activity of aesculetin, using perchloric acid-catalyzed Pechmann reaction and Mannich reaction can produce series of C-4 and C-8 – substituted-aesculetin derivatives. In this paper, the relationship among the structure of coumarin compounds, exposure and dosage was explored using the physiologically-based pharmacokinetic(PBPK) model. The model successfully simulated the pharmacokinetic behaviors of coumarin compounds in human, which providing guidance for the next stage of research.The primary findings are as follows:(1) The construction of PBPK model for coumarin compounds. The PBPK model accurately described the distribution and exposure of compounds in various organs/tissues in human, and further predict their required dosage for anti-lung cancer activities. The basic assumption of PBPK model is that the route of administration is intravenous administration. The model is composed of brain, spleen, pancreas, liver, kidney, lung and heart compartments, and liver is the only eliminating organs. The hepatic clearances were obtained by the in vitro-in vivo extrapolation(IVIVE) methods. All parameters are substituted into the modeland the exposures in lung tissue were simulated. Furthermore, we predicted the requied intravenous dosage of these compounds for their anti-lung cancer activities.(2) Correlation analysis. The exposures(Cmax) of compounds1~15 in lung tissue were well correlated with the tissue/plasma partition coefficients. Intrestingly, the Cmax values of compound 3 and compound 11 were maximum and minimum, respectively. From the structure analysis, compound 3 at the C-4 position introduced lipophilic substitution, which led to the increasing distribution in lung tissue; Moreover, the introduction aminomethyl at the C-8 position of compound 11, increased the metabolic stability of the compounds,. However, due to its lack of lipophilic substitution at C-4 position, the distribution of compound 11 in lung tissue dropped. The predicted initial dosage of compound 15 was lower than others, and the required dosage of compound 1 wasis nearly 20 times than that of compound15. A549, These results were consistent with our previous findings: The cytotoxic activity for A549 cell lines(IC50) of compound 15 was almost 20 times stronger than that of compound 1.In this paper, the relationship of structure, exposure and the dosage was systematically investigated. These findings might help a lot in the development of the coumarin compounds. Ideally, the PBPK model can be viewed as a reservoir of knowledge and data generated from each stage of drug development. The strategic application and development of such an integrated tool would promote developers to make more rational decisions i, and simultaneously improve efficiency and reduce cost.