Abstract
Tanshinol borneol ester (DBZ) is an experimental drug that exhibits efficacious anti-ischemic activity in rats. Although the specific metabolic properties of DBZ are still unknown, previous studies in rats have strongly suggested that DBZ is extensively metabolized after administration and thus probably acts as a prodrug. Because the enzymes involved in drug metabolism differ between humans and rats in isoform composition, expression, and catalytic activity, the pharmacokinetics of the same drug in the two species may also differ. Establishing the differences between DBZ metabolism in human and rat liver microsomes can help to predict DBZ pharmacokinetics in humans and aid in the assessment of its potential efficacy, toxicity, and mechanism of action. In this work, the microsomal stabilities and metabolic kinetics of DBZ in rat and human liver microsomes were compared, and the DBZ metabolites generated in human liver microsomes (HLMs) were identified. The results suggested that DBZ is more stable in HLMs than in rat liver microsomes (RLMs). The intrinsic clearance of DBZ in HLMs was 10- to 17-fold lower than that in RLMs, which indicates lower DBZ clearance in humans. Metabolite analysis suggested that DBZ is hydroxylated by liver microsomal enzymes, resulting in the production of five metabolites. Although the kinetics of metabolite formation in HLMs and RLMs were different, the same metabolites were generated, indicating that the same metabolic pathway is present in both species. The results obtained from this work suggest the potential for DBZ to act as a prodrug with anti-ischemic activity in humans.
Footnotes
This work was supported in part by the Program for Changjiang Scholars and Innovative Research Team in University [Grant IRT0648]; the Major New Medicine Project of the Ministry of Science and Technology of China [Grant 2009ZX09103-121]; the National Science Foundation of China [Grant 20875074]; and the Scientific and Technological Innovation Project of Shaanxi Province [Grants 2007ZDKG-70, 2007ZDKG-76] (13115 Project).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.033381.
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ABBREVIATIONS:
- DBZ
- tanshinol borneol ester
- P450
- cytochrome P450
- RLM
- rat liver microsome
- HLM
- human liver microsome
- LC
- liquid chromatography
- MS
- mass spectrometry
- HPLC
- high-performance liquid chromatography
- MS/MS
- tandem mass spectrometry.
- Received April 3, 2010.
- Accepted June 3, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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