Most cited article - PubMed ID 27732883
Optical isomers of dihydropyridine calcium channel blockers display enantiospecific effects on the expression and enzyme activities of human xenobiotics-metabolizing cytochromes P450
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
