Influence of Amlodipine Enantiomers on Human Microsomal Cytochromes P450: Stereoselective Time-Dependent Inhibition of CYP3A Enzyme Activity.
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Krasulova K, Holas O, Anzenbacher P
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.
- PubMed ID
- 29099769 [ View in PubMed]
- Abstract
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 microM, 14.85 microM, 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 microM, K(inact) 0.065 min(-1)) than S-AML (K(I) 14.06 microM, K(inact) 0.041 min(-1)). R-AML was also a significantly more potent inhibitor of CYP2C9 (K(i) 12.11 microM/S-AML 21.45 microM) and CYP2C19 (K(i) 5.97 microM/S-AML 7.22 muM. 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Amlodipine Cytochrome P450 2C19 Protein Humans NoInhibitorDetails Amlodipine Cytochrome P450 2C9 Protein Humans NoInhibitorDetails