In-vitro stability and metabolism of a tacrine–silibinin codrug
Abstract
Objectives: A 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. Methods: The 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 findings: The codrug remained stable in culture medium (Dulbecco's modified Eagle's medium) over an incubation period of 24 h, 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. Conclusions: This 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.
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Tacrine hemisuccinamide (22) has been proposed as the possible active principle in vivo.
“This has been proposed as the possible active principle in vivo.94”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [94]
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Self-citation
- Authors
- Zenger, K., Chen, X., Decker, M., & Kraus, B.
- Affiliations
- University of Regensburg (DE)
- University of Würzburg (DE)
- Corresponding author
- Kraus, Birgit
- ORCID
- Decker, Michael
- Venue
- Journal of Pharmacy and Pharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-12-01
- Volume
- 65
- Issue
- 12
- Pages
- 1765-1772
- ISSN
- 0022-3573 (ISSN-L)
- 2042-7158
- OpenAlex
- W1523091045
- Cited by
- 13
- References
- 28
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 2 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 2 · 2014: 1 · 2013: 1
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Pharmacy and Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- Funders
- German Research Foundation (DFG DE1546/6-1)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Silymarin and Mushroom Poisoning
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Keywords
- tacrine, silibinin, drug stability, drug metabolism, human liver microsomes, glucuronidation, ester bond cleavage, hepatic stellate cells, mitochondrial toxicity, drug toxicity
- MeSH terms
- Silybin, Cell Survival, Cells, Cultured, Culture Media, Drug Combinations, Drug Stability, Humans, Microsomes, Liver, Mitochondria, Silymarin, Tacrine
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