title: Multiple modes of inhibition of human cytochrome P450 2J2 by dronedarone, amiodarone and their active metabolites.
abstract: Dronedarone, a multiple ion channel blocker is prescribed for the treatment of paroxysmal and persistent atrial fibrillation. While dronedarone does not precipitate toxicities like its predecessor amiodarone, its clinical use has been associated with idiosyncratic hepatic and cardiac adverse effects and drug-drug interactions (DDIs). As dronedarone is a potent mechanism-based inactivator of CYP3A4 and CYP3A5, a question arose if it exerts a similar inhibitory effect on CYP2J2, a prominent cardiac CYP450 enzyme. In this study, we demonstrated that CYP2J2 is reversibly inhibited by dronedarone (Ki=0.034 μM), amiodarone (Ki=4.8μM) and their respective pharmacologically active metabolites namely N-desbutyldronedarone (NDBD) (Ki=0.55 μM) and N-desethylamiodarone (NDEA) (Ki=7.4 μM). Moreover, time-, concentration- and NADPH-dependent irreversible inactivation of CYP2J2 was investigated where inactivation kinetic parameters (KI, kinact) and partition ratio (r) of dronedarone (0.05 μM, 0.034 min(-1), 3.3), amiodarone (0.21 μM, 0.015 min(-1), 20.7) and NDBD (0.48 μM, 0.024 min(-1), 21.7) were observed except for NDEA. The absence of the characteristic Soret peak, lack of recovery of CYP2J2 activity upon dialysis, and biotransformation of dronedarone and NDBD to quinone-oxime reactive metabolites further confirmed the irreversible inactivation of CYP2J2 by dronedarone and NDBD is via the covalent adduction of CYP2J2. Our novel findings illuminate the possible mechanisms of DDIs and cardiac adverse effects due to both reversible inhibition and irreversible inactivation of CYP2J2 by dronedarone, amiodarone and their active metabolites.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Aneesh
authors.initials: A
authors.lastname: Karkhanis
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Hui Yuan
authors.initials: HY
authors.lastname: Lam
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Gopalakrishnan
authors.initials: G
authors.lastname: Venkatesan
authors.affiliation: Singapore Eye Research Institute, The Academia, 20 College Road Discovery Tower Level 6, Singapore 169856.
authors.forename: Siew Kwan
authors.initials: SK
authors.lastname: Koh
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Christina Li Lin
authors.initials: CL
authors.lastname: Chai
authors.affiliation: Singapore Eye Research Institute, The Academia, 20 College Road Discovery Tower Level 6, Singapore 169856.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Department of Cardiology and Cardiac Electrophysiology, National University Heart Centre, 5 Lower Kent Ridge Road, Singapore 119074.
authors.forename: Pipin
authors.initials: P
authors.lastname: Kojodjojo
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543. Electronic address: phaccye@nus.edu.sg.
authors.forename: Eric Chun Yong
authors.initials: EC
authors.lastname: Chan
mesh_terms: D065767:Activation, Metabolic / Q000187:drug effects; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003653:Decarboxylation / Q000187:drug effects; D000077764:Dronedarone; D006801:Humans; D007313:Insecta; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000889:Anti-Arrhythmia Agents; C000717350:CYP2J2 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; C000609888:N-desbutyldronedarone; D011355:Prodrugs; D011994:Recombinant Proteins; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D000077764:Dronedarone; C036116:desethylamiodarone; D000638:Amiodarone
keywords: Amiodarone; Amiodarone (PubChem CID: 2157); Amiodarone hydrochloride (PubChem CID: 441325); Astemizole (PubChem CID: 2247); Atrial fibrillation; CYP2J2; Danazol (PubChem CID: 28417); Dronedarone; Dronedarone (PubChem CID: 208898); Dronedarone hydrochloride (PubChem CID: 219025); Mechanism-based inactivation; N-desbutyldronedarone (PubChem CID: 10255437); N-desethylamiodarone (PubChem CID: 104774); Ritonavir (PubChem CID: 392622)