Physiologically Based Pharmacokinetics of Matrine in the Rat after Oral Administration of Pure Chemical and ACAPHA

• Published in: Drug metabolism and disposition Vol. 37; no. 4; pp. 884 - 891
• Main Authors: Gao, Guanghua, Law, Francis C P
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-04-2009
• Subjects: Administration, Oral; Alkaloids - pharmacokinetics; Animals; Biological and medical sciences; Computer Simulation; Drugs, Chinese Herbal - administration & dosage; Drugs, Chinese Herbal - pharmacokinetics; Gas Chromatography-Mass Spectrometry; Male; Medical sciences; Models, Biological; Pharmacology. Drug treatments; Quinolizines - pharmacokinetics; Rats; Rats, Sprague-Dawley; Vertebrata; Mammalia; Rat; Animal; Rodentia; Oral administration; Pharmacokinetics
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.108.023788

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.