Endocrine Abstracts

Several of currently used drugs are chiral compounds. Majority of them are clinically administered as a racemic (equimolar) mixture of enantiomers. Individual enantiomers of one drug can qualitatively and quantitatively differ in their biological activities (pharmacology, toxicology, pharmacokinetics, etc.). Therefore, enantiopure drugs have been developed and introduced to the therapy. Statins are drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase. Atorvastatin, rosuvastatin, and fluvastatin are the most often prescribed statins. They have two chiral centres, thus they form four enantiomers (3R5R, 3R5S, 3S5R, and 3S5S). They are marketed as a racemic mixture of these enantiomers; however their enantiopure forms have been introduced to clinic recently (3R5R-atorvastatin, 3R5S-rosuvastatin, and 3R5S-fluvastatin). In this study, we investigated enantiospecific interactions of all four enantiopure forms of atorvastin, rosuvastatin, and fluvastatin with main transcriptional regulators of drug-metabolizing enzymes – aryl hydrocarbon receptor (AhR), glucocorticoid receptor (GR), and pregnane X receptor (PXR). Agonist and antagonist activities of tested compounds towards AhR, PXR, and GR were determined using human reporter cell lines. Moreover, we have tested enantiospecific effects of statins on the expression of drug-metabolising enzymes CYPs on mRNA and protein level in primary human hepatocytes.

Disclosure: Financial support from Czech Scientific agency 13-01809S and Students project of Palacky University Olomouc PrF-2015-003 is greatly acknowledged.