Physiologically based pharmacokinetics of matrine in the rat after oral administration of pure chemical and ACAPHA

Abstract

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.

Fig. 1.

Chemical structure of matrine.

Fig. 2.

Schematic diagram of the physiologically based pharmacokinetic model used to simulate the disposition of matrine in plasma and tissues of rats after administration of pure matrine or ACAPHA. C, matrine concentrations (ng/g or ml); Q, plasma flow rates (l/h). Subscripts refer to tissues (see Appendix).

Fig. 3.

Comparison of model-simulated and experimental matrine concentrations in the tissue/plasma of rats after receiving pure matrine or ACAPHA. a, plasma; b, kidney; c, spleen; d, brain; e, heart; f, muscle; g, lung; h, liver; i, fat. •, experimental data of rats receiving 15 mg/kg pure matrine; □, experimental data of rats receiving 3.8 g/kg ACAPHA; ▪, experimental data of rats receiving 0.38 g/kg ACAPHA. Data points, means ± S.D. of the experimental plasma/tissue concentrations from three different rats; –– –– ––, model-simulated matrine concentrations of rats receiving 15 mg/kg pure matrine; ———, model-simulated matrine concentrations of rats receiving 3.8 g/kg ACAPHA; —--—--, model-simulated matrine concentrations of rats receiving 0.38 g/kg ACAPHA.

Fig. 3.

Comparison of model-simulated and experimental matrine concentrations in the tissue/plasma of rats after receiving pure matrine or ACAPHA. a, plasma; b, kidney; c, spleen; d, brain; e, heart; f, muscle; g, lung; h, liver; i, fat. •, experimental data of rats receiving 15 mg/kg pure matrine; □, experimental data of rats receiving 3.8 g/kg ACAPHA; ▪, experimental data of rats receiving 0.38 g/kg ACAPHA. Data points, means ± S.D. of the experimental plasma/tissue concentrations from three different rats; –– –– ––, model-simulated matrine concentrations of rats receiving 15 mg/kg pure matrine; ———, model-simulated matrine concentrations of rats receiving 3.8 g/kg ACAPHA; —--—--, model-simulated matrine concentrations of rats receiving 0.38 g/kg ACAPHA.

Fig. 4.

Time course of matrine plasma concentrations in rats receive: a, bolus intravenous injection of 40 mg/kg pure matrine; or b, single oral dose of 40 mg/kg pure matrine. Solid line, model simulation. Data points, mean of experimental data. They were read digitally from the publication of Wu et al. (2003).