Zenger, Katharina and Chen, Xinyu and Decker, Michael and Kraus, Birgit (2013) In-vitro stability and metabolism of a tacrine-silibinin codrug. JOURNAL OF PHARMACY AND PHARMACOLOGY, 65 (12). pp. 1765-1772. ISSN 0022-3573, 2042-7158
Full text not available from this repository. (Request a copy)Abstract
ObjectivesA tacrine-silibinin codrug showed promising results in pharmacological and toxicity testing, superior to an equimolar mixture of tacrine and silibinin. The aim of this study was to get more information about its stability, possible degradation products, metabolites, and especially its active principle in vitro and in vivo. MethodsThe stability of the codrug was analysed under in-vitro assay conditions. Additionally, its metabolism was investigated using pooled human liver microsomes. Metabolites were identified via liquid chromatography-high resolution electrospray ionization mass spectrometry. Furthermore, the influence of one of the main cleavage products, tacrine hemi succinamide, on viability and mitochondria of hepatic stellate cells was analysed. Key findingsThe codrug remained stable in culture medium (Dulbecco's modified Eagle's medium) over an incubation period of 24h, whereas exposition to microsomal enzymes led to rapid cleavage of the ester bond to form silibinin and a tacrine hemi succinamide. In addition, glucuronidated metabolites of both silibinin and the codrug were detected. For the tacrine hemi succinamide, no effects were observed with regard to cell viability and mitochondrial impairment. ConclusionsThis study helps understand and interpret previous results concerning the effects and the absence of toxicity of the tacrine-silibinin codrug and supplies important information for further identification of the active principles of the codrug in vivo.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ALZHEIMERS-DISEASE; CELL-DEATH; RAT; HEPATOTOXICITY; VIVO; TETRAHYDROAMINOACRIDINE; PHARMACOKINETICS; PATHOGENESIS; HEPATOCYTES; FLUVOXAMINE; codrug; microsomal metabolites; silibinin; stability; tacrine |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical Biology (Prof. Heilmann) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Mar 2020 10:12 |
| Last Modified: | 23 Mar 2020 10:12 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15555 |
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