Physiologically based pharmacokinetics of matrine in the rat after oral administration of pure chemical and ACAPHA.
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.
Gao
Guanghua
G
Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada, V5A 1S6.
Law
Francis C P
FC
D000284:Administration, Oral; D000470:Alkaloids / Q000493:pharmacokinetics*; D000818:Animals; D003198:Computer Simulation; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D008954:Models, Biological; D011807:Quinolizines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000093842:Matrines
D000470:Alkaloids; D004365:Drugs, Chinese Herbal; D011807:Quinolizines; C541947:antitumor A; D000093842:Matrines