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Drug-interaction potential of LK-935, the novel non-statin type cholesterol lowering agentMonostory, Katalin ...The widely prescribed lipid lowering statins are considered to be relatively safe drugs. However, the risk of severe myopathy and drug-interactions as a consequence of statin therapy provides a ... challenge for development of novel cholesterol lowering agents, targeting enzymes other than HMG-CoA reductase. The novel pyridylethanol(phenylethyl)amine derivative LK-935, blocking lanosterol 14alpha-demethylase, was demonstrated to efficiently reduce cholesterol biosynthesis. The drug-interaction potential of LK-935 was investigated and compared to that of atorvastatin and rosuvastatin in primary human hepatocytes. Clear evidence was provided for the induction of CYP3A4 by LK-935. LK-935 was proved to be a potent hPXR activator as prerequisite for the transcriptional activation of CYP3A4 gene; however, the rapid metabolism of LK-935 in primary hepatocytes prevented the maximal CYP3A4 induction. Therefore the induction of CYP3A4 by LK-935 may be prone to mild or negligibledrug-interaction. However, due to the fact that CYP3A4 and also CYP2C9 play a significant role in LK-935 metabolism, the inhibition of these cytochrome P450s by coadministered drugs may lead to some increase in LK-935 concentration required for the potent induction of CYP3A4. Rosuvastatin was found to increase hCAR-mediated transcription of CYP3A4, CYP2C9, and CYP2B6 genes, predicting the consequent potential for drug-interactions with several coadministered drugs. Activation of hCAR and hPXR by atorvastatin and the subsequent induction of not only CYP2B6 and CYP3A4, but also of CYP2C9 presentan additional target by which atorvastatin, a widely used cholesterol lowering drug, can modify the kinetics of numerous drugs.Source: Drug metabolism and disposition. - ISSN 0090-9556 (Vol. 37, issue 2, 2009, str. 375-385)Type of material - article, component part ; adult, seriousPublish date - 2009Language - englishCOBISS.SI-ID - 24945625
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Monostory, Katalin | |
Pascussi, Jean-Marc | |
Szabó, Pál, kemik | |
Temesvári, Manna | |
Kohalmy, K. | |
Ačimovič, Jure | 28352 |
Kocjan, Darko | 09905 |
Kuzman, Drago | 18355 |
Wilzewski, Britta | |
Bernhardt, Rita | |
Kóbori, László | |
Rozman, Damjana, 1960- | 06013 |
Source: Personal bibliographies
and: SICRIS
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