Comparative pharmacokinetics of matrine: pure chemical vs. crude chemical in Acapha®

Acapha®, an herbal product used for treating esophageal cancer in China, is undergoing clinical trials as a chemopreventive agent for lung cancer at the B.C. Cancer Agency (BCCA). Little is known of the pharmacokinetics (PK) of Acapha because most of the PK tools available today are developed for a single chemical entity not a chemical mixture such as Acapha. The purposes of the present study were to demonstrate the feasibility of using matrine as a chemical marker to study the PK of Acapha, to compare the PK of pure matrine with the PK of crude matrine in Acapha, to elucidate the underlying mechanism of matrine absorption and metabolism, and to develop and validate a physiologically based pharmacokinetic (PBPK) model of matrine for rats and humans. A generic matrine PBPK model consisting of 12 compartments was developed and validated in the rat. The rat model was then scaled to the model of a standard human by replacing the parameters in the rat model with those of humans. The human PBPK model was able to describe closely the time course of matrine concentrations in plasma (or urine) reported in the literature or from a human study at the BCCA. The BCCA datasets also were fitted to a 2-compartment, clearance-volume classical PK model. Model-derived PK parameters showed that about 35-48% of the matrine administered orally was absorbed by humans, which was consistent with the results of the in vitro Caco-2 cell transport study. The PBPK model also predicted that matrine was not metabolized significantly by humans confirming the results of the in vitro liver microsomal incubation studies. When the various CYP1A2, 2C19, 3A4, 2C9, and 2D6 probe substrates were incubated separately with human liver microsomes in the presence or absence of Acapha extract, the metabolic rates of the CYP probes were not found to change significantly. Results of the present studies demonstrate that Caco-2 cell monolayer and PBPK model can provide important insights to the kinetics of Acapha® in humans. These scientific tools should be integrated with the herbal product development paradigm because they may render the development processes more rational and efficient.