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