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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 K i 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 (K I 8.22 µM, K inact 0.065 min -1 ) than S -AML (K I 14.06 µM, K inact 0.041 min -1 ). R -AML was also a significantly more potent inhibitor of CYP2C9 (K i 12.11 µM/ S -AML 21.45 µM) and CYP2C19 (K i 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.

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