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.

• Keywords
• amlodipine, cytochrome P450, drug–drug interactions, enantiomers, enzyme inhibition, stereoselectivity,
• MeSH
• Amlodipine chemistry   pharmacology   MeSH
• Hydroxylation MeSH
• Cytochrome P-450 CYP3A Inhibitors chemistry   pharmacology   MeSH
• Cytochrome P-450 Enzyme Inhibitors chemistry   pharmacology   MeSH
• Microsomes, Liver metabolism   MeSH
• Kinetics MeSH
• Drug Interactions MeSH
• Humans MeSH
• Midazolam metabolism   MeSH
• Molecular Structure MeSH
• Molecular Docking Simulation MeSH
• Stereoisomerism MeSH
• Cytochrome P-450 Enzyme System metabolism   MeSH
• Thermodynamics MeSH
• Binding Sites MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amlodipine MeSH
• Cytochrome P-450 CYP3A Inhibitors MeSH
• Cytochrome P-450 Enzyme Inhibitors MeSH
• Midazolam MeSH
• Cytochrome P-450 Enzyme System 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.

• Keywords
• drug-metabolizing enzymes, farnesol, inhibition, nerolidol,
• MeSH
• Farnesol chemistry   pharmacology   MeSH
• Inhibitory Concentration 50 MeSH
• Cytochrome P-450 Enzyme Inhibitors chemistry   pharmacology   MeSH
• Liver enzymology   MeSH
• Kinetics MeSH
• Rats MeSH
• Humans MeSH
• Sesquiterpenes chemistry   pharmacology   MeSH
• Subcellular Fractions enzymology   MeSH
• Cytochrome P-450 Enzyme System metabolism   MeSH
• Xenobiotics metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Farnesol MeSH
• Cytochrome P-450 Enzyme Inhibitors MeSH
• nerolidol MeSH Browser
• Sesquiterpenes MeSH
• Cytochrome P-450 Enzyme System MeSH
• Xenobiotics 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 pharmacology   MeSH
• Cytochrome P-450 CYP3A biosynthesis   MeSH
• Cytochrome P-450 CYP2A6 biosynthesis   MeSH
• Cytochrome P-450 CYP2B6 biosynthesis   MeSH
• Adult MeSH
• Enzyme Induction drug effects   MeSH
• Fluvastatin MeSH
• Hepatocytes cytology   enzymology   MeSH
• Indoles pharmacology   MeSH
• Cytochrome P-450 CYP2B6 Inducers pharmacology   MeSH
• Cytochrome P-450 CYP3A Inducers pharmacology   MeSH
• Fatty Acids, Monounsaturated pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Pregnane X Receptor MeSH
• Rosuvastatin Calcium pharmacology   MeSH
• Aged MeSH
• Stereoisomerism MeSH
• Receptors, Steroid biosynthesis   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Atorvastatin MeSH
• CYP2A6 protein, human MeSH Browser
• CYP2B6 protein, human MeSH Browser
• CYP3A4 protein, human MeSH Browser
• Cytochrome P-450 CYP3A MeSH
• Cytochrome P-450 CYP2A6 MeSH
• Cytochrome P-450 CYP2B6 MeSH
• Fluvastatin MeSH
• Indoles MeSH
• Cytochrome P-450 CYP2B6 Inducers MeSH
• Cytochrome P-450 CYP3A Inducers MeSH
• Fatty Acids, Monounsaturated MeSH
• Pregnane X Receptor MeSH
• Rosuvastatin Calcium MeSH
• Receptors, Steroid MeSH