Influence of Amlodipine Enantiomers on Human Microsomal Cytochromes P450: Stereoselective Time-Dependent Inhibition of CYP3A Enzyme Activity

Molecules. 2017 Nov 3;22(11):1879. doi: 10.3390/molecules22111879.


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 terms

  • Amlodipine / chemistry*
  • Amlodipine / pharmacology*
  • Binding Sites
  • Cytochrome P-450 CYP3A Inhibitors / chemistry
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology
  • Cytochrome P-450 Enzyme Inhibitors / chemistry*
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Interactions
  • Humans
  • Hydroxylation
  • Kinetics
  • Microsomes, Liver / metabolism
  • Midazolam / metabolism
  • Molecular Docking Simulation
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thermodynamics


  • Cytochrome P-450 CYP3A Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Amlodipine
  • Cytochrome P-450 Enzyme System
  • Midazolam