Inactivation of Human Cytochrome P450 3A4 and 3A5 by Dronedarone and N-Desbutyl Dronedarone.

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Hong Y, Chia YM, Yeo RH, Venkatesan G, Koh SK, Chai CL, Zhou L, Kojodjojo P, Chan EC

Inactivation of Human Cytochrome P450 3A4 and 3A5 by Dronedarone and N-Desbutyl Dronedarone.

Mol Pharmacol. 2016 Jan;89(1):1-13. doi: 10.1124/mol.115.100891. Epub 2015 Oct 21.

PubMed ID

26490246 [ View in PubMed

]

Abstract

Dronedarone is an antiarrhythmic agent approved in 2009 for the treatment of atrial fibrillation. An in-house preliminary study demonstrated that dronedarone inhibits cytochrome P450 (CYP) 3A4 and 3A5 in a time-dependent manner. This study aimed to investigate the inactivation of CYP450 by dronedarone. We demonstrated for the first time that both dronedarone and its main metabolite N-desbutyl dronedarone (NDBD) inactivate CYP3A4 and CYP3A5 in a time-, concentration-, and NADPH-dependent manner. For the inactivation of CYP3A4, the inactivator concentration at the half-maximum rate of inactivation and inactivation rate constant at an infinite inactivator concentration are 0.87 microM and 0.039 minute(-1), respectively, for dronedarone, and 6.24 microM and 0.099 minute(-1), respectively, for NDBD. For CYP3A5 inactivation, the inactivator concentration at the half-maximum rate of inactivation and inactivation rate constant at an infinite inactivator concentration are 2.19 microM and 0.0056 minute(-1) for dronedarone and 5.45 microM and 0.056 minute(-1) for NDBD. The partition ratios for the inactivation of CYP3A4 and CYP3A5 by dronedarone are 51.1 and 32.2, and the partition ratios for the inactivation of CYP3A4 and CYP3A5 by NDBD are 35.3 and 36.6. Testosterone protected both CYP3A4 and CYP3A5 from inactivation by dronedarone and NDBD. Although the presence of Soret peak confirmed the formation of a quasi-irreversible metabolite-intermediate complex between dronedarone/NDBD and CYP3A4/CYP3A5, partial recovery of enzyme activity by potassium ferricyanide illuminated an alternative irreversible mechanism-based inactivation (MBI). MBI of CYP3A4 and CYP3A5 was further supported by the discovery of glutathione adducts derived from the quinone oxime intermediates of dronedarone and NDBD. In conclusion, dronedarone and NDBD inactivate CYP3A4 and CYP3A5 via unique dual mechanisms of MBI and formation of the metabolite-intermediate complex. Our novel findings contribute new knowledge for future investigation of the underlying mechanisms associated with dronedarone-induced hepatotoxicity and clinical drug-drug interactions.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Dronedarone	Cytochrome P450 3A5	Protein	Humans	Unknown	Substrate Inhibitor	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Abemaciclib Dronedarone	The serum concentration of Abemaciclib can be increased when it is combined with Dronedarone.
Acalabrutinib Dronedarone	The serum concentration of Acalabrutinib can be increased when it is combined with Dronedarone.
Acenocoumarol Dronedarone	The serum concentration of Acenocoumarol can be increased when it is combined with Dronedarone.
Alectinib Dronedarone	The serum concentration of Alectinib can be increased when it is combined with Dronedarone.
Alpelisib Dronedarone	The serum concentration of Alpelisib can be increased when it is combined with Dronedarone.