ACAPHA, a botanical
drug for the treatment of human
esophageal cancer in China, is under investigation as a
lung cancer chemoprevention agent at the BC
Cancer Agency (Vancouver, BC, Canada). Little or no information is available on the pharmacokinetics of
ACAPHA in animals. The objectives of this study were as follows: to examine the disposition kinetics of
matrine, a bioactive marker of
ACAPHA in the rat; to develop a physiologically based pharmacokinetic (PBPK) model for pure
matrine; and to characterize the absorption and clearance of crude
matrine in
ACAPHA-treated rats using the PBPK model. Pure
matrine (15 mg/kg) or crude
matrine in the form of
ACAPHA (0.38 or 3.8 g/kg) was administered to the rat by gavages. The rats were sacrificed at different time points postdosing. Blood and major organs were removed from the rat, extracted with
toluene/
butanol, and quantified for
matrine using gas chromatography-mass spectrometry. An 11-compartment, flow-limited PBPK model of
matrine was developed. The PBPK model was able to simulate closely the empirical data of rats treated with pure
matrine. Because the absorption and clearance of crude
matrine in
ACAPHA-treated rats could not be parameterized a priori, they were estimated by fitting the experimental data to the PBPK model. Results of the study show that pure
matrine is absorbed and eliminated by the rat at faster rates than crude
matrine. Moreover, the
ACAPHA matrix may change the pharmacokinetics of
matrine in the rat significantly. The PBPK model is a valuable tool to gain insights into the disposition kinetics of a botanical
drug.