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