Drug-Drug Interactions between Atorvastatin and Dronedarone Mediated by Monomeric CYP3A4

Ilia G. Denisov, Javier L. Baylon, Yelena V. Grinkova, Emad Tajkhorshid, Stephen G. Sligar

Research output: Contribution to journalArticle

Abstract

Heterotropic interactions between atorvastatin (ARVS) and dronedarone (DND) have been deciphered using global analysis of the results of binding and turnover experiments for pure drugs and their mixtures. The in vivo presence of atorvastatin lactone (ARVL) was explicitly taken into account by using pure ARVL in analogous experiments. Both ARVL and ARVS inhibit DND binding and metabolism, while a significantly higher affinity of CYP3A4 for ARVL makes the latter the main modulator of activity (effector) in this system. Molecular dynamics simulations reveal significantly different modes of interactions of DND and ARVL with the substrate binding pocket and with a peripheral allosteric site. Interactions of both substrates with residues F213 and F219 at the allosteric site play a critical role in the communication of conformational changes induced by effector binding to productive binding of the substrate at the catalytic site.

Original languageEnglish (US)
Pages (from-to)805-816
Number of pages12
JournalBiochemistry
Volume57
Issue number5
DOIs
StatePublished - Feb 6 2018

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Drug interactions
Cytochrome P-450 CYP3A
Drug Interactions
Lactones
Pharmaceutical Preparations
Allosteric Site
Substrates
Molecular Dynamics Simulation
dronedarone
Atorvastatin Calcium
Metabolism
Modulators
Molecular dynamics
Catalytic Domain
Experiments
Communication
Computer simulation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Drug-Drug Interactions between Atorvastatin and Dronedarone Mediated by Monomeric CYP3A4. / Denisov, Ilia G.; Baylon, Javier L.; Grinkova, Yelena V.; Tajkhorshid, Emad; Sligar, Stephen G.

In: Biochemistry, Vol. 57, No. 5, 06.02.2018, p. 805-816.

Research output: Contribution to journalArticle

Denisov, Ilia G. ; Baylon, Javier L. ; Grinkova, Yelena V. ; Tajkhorshid, Emad ; Sligar, Stephen G. / Drug-Drug Interactions between Atorvastatin and Dronedarone Mediated by Monomeric CYP3A4. In: Biochemistry. 2018 ; Vol. 57, No. 5. pp. 805-816.
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