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.
Footnotes
-
This work was supported by the National Institutes of Health National Cancer Institute [Grant U01-CA96109].
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.108.023788.
-
ABBREVIATIONS: PK, pharmacokinetics; GC, gas chromatography; MS, mass spectrometry; PBPK, physiologically based pharmacokinetics; LLOQ, lower limit of quantification; AUC, area under the concentration-time curve; BLPLR, blood/plasma ratio; ka, absorption rate constant; CL, renal clearance; EH, hepatic extraction ratio; kf, fecal excretion rate constant; F, bioavailability factor; MPE, mean prediction error; LNSC, log-normalized sensitivity coefficient; tlag, lag time; Vdss, volume of distribution at steady-state.
-
↵1 Current Affiliation: Department of Biology, Hong Kong Baptist University, Kowloon, Hong Kong, SAR, China.
- Received August 13, 2008.
- Accepted January 6, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|