Amlodipine (AML) is available as a racemate, i.e., a mixture of R- and S-enantiomers. Its inhibitory potency towards nine cytochromes P450 (CYP) was studied to evaluate the drug-drug interactions between the enantiomers. Enzyme inhibition was evaluated using specific CYP substrates in human liver microsomes. With CYP3A, both enantiomers exhibited reversible and time-dependent inhibition. S-AML was a stronger reversible inhibitor of midazolam hydroxylation: the Ki values of S- and R-AML were 8.95 µM, 14.85 µM, respectively. Computational docking confirmed that the enantiomers interact differently with CYP3A: the binding free energy of S-AML in the active site was greater than that for R-AML (-7.6- vs. -6.7 kcal/mol). Conversely, R-AML exhibited more potent time-dependent inhibition of CYP3A activity (KI 8.22 µM, Kinact 0.065 min-1) than S-AML (KI 14.06 µM, Kinact 0.041 min-1). R-AML was also a significantly more potent inhibitor of CYP2C9 (Ki 12.11 µM/S-AML 21.45 µM) and CYP2C19 (Ki 5.97 µM/S-AML 7.22 μM. In conclusion, results indicate that clinical use of S-AML has an advantage not only because of greater pharmacological effect, but also because of fewer side effects and drug-drug interactions with cytochrome P450 substrates due to absence of R-AML.

• Klíčová slova
• amlodipine, cytochrome P450, drug–drug interactions, enantiomers, enzyme inhibition, stereoselectivity,
• MeSH
• amlodipin chemie   farmakologie   MeSH
• hydroxylace MeSH
• inhibitory cytochromu P450 CYP3A chemie   farmakologie   MeSH
• inhibitory cytochromu P450 chemie   farmakologie   MeSH
• jaterní mikrozomy metabolismus   MeSH
• kinetika MeSH
• lékové interakce MeSH
• lidé MeSH
• midazolam metabolismus   MeSH
• molekulární struktura MeSH
• simulace molekulového dockingu MeSH
• stereoizomerie MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• termodynamika MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amlodipin MeSH
• inhibitory cytochromu P450 CYP3A MeSH
• inhibitory cytochromu P450 MeSH
• midazolam MeSH
• systém (enzymů) cytochromů P-450 MeSH

Sesquiterpenes, 15-carbon compounds formed from three isoprenoid units, are the main components of plant essential oils. Sesquiterpenes occur in human food, but they are principally taken as components of many folk medicines and dietary supplements. The aim of our study was to test and compare the potential inhibitory effect of acyclic sesquiterpenes, trans-nerolidol, cis-nerolidol and farnesol, on the activities of the main xenobiotic-metabolizing enzymes in rat and human liver in vitro. Rat and human subcellular fractions, relatively specific substrates, corresponding coenzymes and HPLC, spectrophotometric or spectrofluorometric analysis of product formation were used. The results showed significant inhibition of cytochromes P450 (namely CYP1A, CYP2B and CYP3A subfamilies) activities by all tested sesquiterpenes in rat as well as in human hepatic microsomes. On the other hand, all tested sesquiterpenes did not significantly affect the activities of carbonyl-reducing enzymes and conjugation enzymes. The results indicate that acyclic sesquiterpenes might affect CYP1A, CYP2B and CYP3A mediated metabolism of concurrently administered drugs and other xenobiotics. The possible drug-sesquiterpene interactions should be verified in in vivo experiments.

• Klíčová slova
• drug-metabolizing enzymes, farnesol, inhibition, nerolidol,
• MeSH
• farnesol chemie   farmakologie   MeSH
• inhibiční koncentrace 50 MeSH
• inhibitory cytochromu P450 chemie   farmakologie   MeSH
• játra enzymologie   MeSH
• kinetika MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• seskviterpeny chemie   farmakologie   MeSH
• subcelulární frakce enzymologie   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• xenobiotika metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• farnesol MeSH
• inhibitory cytochromu P450 MeSH
• nerolidol MeSH Prohlížeč
• seskviterpeny MeSH
• systém (enzymů) cytochromů P-450 MeSH
• xenobiotika MeSH

Atorvastatin, fluvastatin and rosuvastatin are drugs used for treatment of hypercholesterolemia. They cause numerous drug-drug interactions by inhibiting and inducing drug-metabolizing cytochromes P450. These three statins exist in four optical forms, but they are currently used as enantiopure drugs, i.e., only one single enantiomer. There are numerous evidences that efficacy, adverse effects and toxicity of drugs may be enantiospecific. Therefore, we investigated the effects of optical isomers of atorvastatin, fluvastatin and rosuvastatin on the expression of drug-metabolizing P450s in primary human hepatocytes, using western blots and RT-PCR for measurement of proteins and mRNAs, respectively. The activity of P450 transcriptional regulators, including pregnane X receptor (PXR), aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR), was assessed by gene reporter assays and EMSA. Transcriptional activity of AhR was not influenced by any statin tested. Basal transcriptional activity of GR was not affected by tested statins, but dexamethasone-inducible activity of GR was dose-dependently and enantioselectively inhibited by fluvastatin. Basal and ligand-inducible transcriptional activity of PXR was dose-dependently influenced by all tested statins, and the potency and efficacy between individual optical isomers varied depending on statin and optical isomer. The expression of CYP1A1 and CYP1A2 in human hepatocytes was not influenced by tested statins. All statins induced CYP2A6, CYP2B6 and CYP3A4, and the effects on CYP2C9 were rather modulatory. The effects varied between statins and enantiomers and induction potency decreased in order: atorvastatin (RR>RS = SR>SS) > fluvastatin (SR>RS = SS>RR) >> rosuvastatin (only RS active). The data presented here might be of toxicological and clinical importance.

• MeSH
• atorvastatin farmakologie   MeSH
• cytochrom P-450 CYP3A biosyntéza   MeSH
• cytochrom P450 CYP2A6 biosyntéza   MeSH
• cytochrom P450 CYP2B6 biosyntéza   MeSH
• dospělí MeSH
• enzymová indukce účinky léků   MeSH
• fluvastatin MeSH
• hepatocyty cytologie   enzymologie   MeSH
• indoly farmakologie   MeSH
• induktory cytochromu P450 CYP2B6 farmakologie   MeSH
• induktory cytochromu P450 CYP3A farmakologie   MeSH
• kyseliny mastné mononenasycené farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• pregnanový X receptor MeSH
• rosuvastatin kalcium farmakologie   MeSH
• senioři MeSH
• stereoizomerie MeSH
• steroidní receptory biosyntéza   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• atorvastatin MeSH
• CYP2A6 protein, human MeSH Prohlížeč
• CYP2B6 protein, human MeSH Prohlížeč
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2A6 MeSH
• cytochrom P450 CYP2B6 MeSH
• fluvastatin MeSH
• indoly MeSH
• induktory cytochromu P450 CYP2B6 MeSH
• induktory cytochromu P450 CYP3A MeSH
• kyseliny mastné mononenasycené MeSH
• pregnanový X receptor MeSH
• rosuvastatin kalcium MeSH
• steroidní receptory MeSH