Identification of metabolic pathways and enzyme systems involved in the in vitro human hepatic metabolism of dronedarone, a potent new oral antiarrhythmic drug

Klieber, Sylvie; Arabeyre-Fabre, Catherine; Moliner, Patricia; Marti, Eric; Mandray, Martine; Ngo, Robert; Ollier, Céline; Brun, Priscilla; Fabre, Gérard

doi:10.1002/prp2.44

Cited by 22 publications

(26 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our in vitro assay using rCYP450 confirmed that dronedarone is extensively metabolized by CYP3A4 and CYP3A5, in agreement with a previous report (Klieber et al, 2014). Additionally, we found that although CYP2D6 and CYP2C19 contribute to the metabolism of dronedarone, CYP2C8, CYP2C9, CYP1A2, and CYP2E1 do not metabolize dronedarone.…”

Section: Discussionsupporting

confidence: 92%

“…Our in vitro observation that NDBD is the main metabolite of dronedarone is consistent with clinical data that the plasma systemic exposure of NDBD is approximately half that of its parent drug following oral administration (USFDA, 2008). Notably, NDBD is pharmacologically active in vivo (USFDA, 2008) and is further oxidized by CYP3A4 (Klieber et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…1C), the main metabolite formed primarily by CYP3A is pharmacologically active and has a similar plasma exposure to its parent drug (Klieber et al, 2014). Although the overall metabolic pathway of dronedarone has been reported recently (Klieber et al, 2014), no study investigates the mechanism of inhibition of CYP450 by dronedarone thus far.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2015

View full text Add to dashboard Cite

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 NADPHdependent 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 mM and 0.039 minute 21 , respectively, for dronedarone, and 6.24 mM and 0.099 minute 21, respectively, for NDBD. For CYP3A5 inactivation, the inactivator concentration at the halfmaximum rate of inactivation and inactivation rate constant at an infinite inactivator concentration are 2.19 mM and 0.0056 minute 21 for dronedarone and 5.45 mM and 0.056 minute 21 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.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Both drugs are metabolized by CYP3A4 (37, 40–44) as shown in Figure 1, and both are involved in drug-drug interactions (36–39, 41). Importantly, the highly lever-aged effects of Multaq interactions with multiple cardiac ion channels(45) make interaction with other commonly prescribed medications, such as Lipitor, extremely relevant.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

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 significantly higher affinity of CYP3A4 towards ARVL makes the latter the main effector in this system. Molecular dynamics simulations reveal significantly different modes of interactions of DND and ARVL with the substrate binding pocket and with the peripheral allosteric site. Interactions of both substrates with residues F213 and F219 at the allosteric site play the most important role in the communication of conformational changes induced by effector binding towards productive binding of substrate at the catalytic site.

show abstract

“…It has been reported that dronedarone can be detected within 24 h incubation in metabolically competent human primary hepatocytes (Klieber et al 2014). Therefore, in the current study, the cytotoxicity of dronedarone was initially investigated at various concentrations below 10 μM for a longer time (24 h).…”

Section: Resultsmentioning

confidence: 99%

The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone

Chen

Bryant

et al. 2018

Arch Toxicol

View full text Add to dashboard Cite

Dronedarone is used to treat patients with cardiac arrhythmias and has been reported to be associated with liver injury. Our previous mechanistic work demonstrated that DNA damage-induced apoptosis contributes to the cytotoxicity of dronedarone. In this study, we examined further the underlying mechanisms and found that after a 24-h treatment of HepG2 cells, dronedarone caused cytotoxicity, G1-phase cell cycle arrest, suppression of topoisomerase II, and DNA damage in a concentration-dependent manner. We also investigated the role of cytochrome P450s (CYPs)-mediated metabolism in the dronedarone-induced toxicity using our previously established HepG2 cell lines expressing individually 14 human CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrated that CYP3A4, 3A5, and 2D6 were the major enzymes that metabolize dronedarone, and that CYP3A7, 2E1, 2C19, 2C18, 1A1, and 2B6 also metabolize dronedarone, but to a lesser extent. Our data showed that the cytotoxicity of dronedarone was decreased in CYP3A4-, 3A5-, or 2D6-overexpressing cells compared to the control HepG2 cells, indicating that the parent dronedarone has higher potency than the metabolites to induce cytotoxicity in these cells. In contrast, cytotoxicity was increased in CYP1A1-overexpressing cells, demonstrating that CYP1A1 exerts an opposite effect in dronedarone's toxicity, comparing to CYP3A4, 3A5, or 2D6. We also studied the involvement of topoisomerase II in dronedarone-induced toxicity, and demonstrated that the overexpression of topoisomerase II caused an increase in cell viability and a decrease in γ-H2A.X induction, suggesting that suppression of topoisomerase II may be one of the mechanisms involved in dronedarone-induced liver toxicity.

show abstract

Identification of metabolic pathways and enzyme systems involved in the in vitro human hepatic metabolism of dronedarone, a potent new oral antiarrhythmic drug

Cited by 22 publications

References 19 publications

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

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

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

The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone

Contact Info

Product

Resources

About