title: Absence of interactive effects of trans-1,2-cyclohexanediol, a major metabolite of the side-chain of candesartan cilexetil, on digoxin-induced arrhythmias in dogs.
abstract: trans-1,2-Cyclohexanediol, the major metabolite of the cilexetil moiety of candesartan cilexetil (CC), has been reported to have potent pro-arrhythmic effects in dogs with congestive heart failure (CHF), especially when co-administered with digoxin. To verify this and to clarify the clinical relevance and the underlying mechanisms, a series of in vivo and in vitro experiments was conducted. When CC up to 300 mg/kg was administered orally to intact dogs, no changes in the electrocardiograms (ECG) or the required cumulative doses of ouabain to induce ventricular arrhythmias were observed. In dogs with CHF, intravenous bolus administration of trans-1,2-cyclohexanediol at 4 mg/kg followed by continuous infusion at 0.1 mg x kg(-)(1) x min(-)(1) had no effects on the ECG parameters, the type, incidence, and onset time of digoxin-induced arrhythmias or the metabolism of digoxin. In an in vitro experiment using isolated guinea pig papillary muscle, trans-1,2-cyclohexanediol (1 - 100 micromol/L) showed no effects on any parameter of the action potentials. Because no effects were observed in these experiments where the exposure levels of trans-1,2-cyclohexanediol were extremely high compared to those in humans given the maximum therapeutic dose of CC, it is unlikely that CC would induce arrhythmias in clinical use even in patients treated with cardiac glycosides.
authors.affiliation: Drug Safety Research Center, Takeda Chemical Industries, Ltd, Osaka, Japan. Yamamoto_Keiji@takeda.co.jp
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Takahito
authors.initials: T
authors.lastname: Kitayoshi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.forename: Fumio
authors.initials: F
authors.lastname: Chatani
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000097:blood* / Q000139:chemically induced; D001562:Benzimidazoles / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000378:metabolism*; D003511:Cyclohexanols / Q000097:blood* / Q000494:pharmacology*; D004077:Digoxin / Q000097:blood* / Q000633:toxicity; D004285:Dogs; D004347:Drug Interactions / Q000502:physiology; D006168:Guinea Pigs; D006333:Heart Failure / Q000097:blood / Q000139:chemically induced; D066298:In Vitro Techniques; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles
chemical_list: D001562:Benzimidazoles; D001713:Biphenyl Compounds; D003511:Cyclohexanols; D013777:Tetrazoles; D004077:Digoxin; C064619:1,2-cyclohexanediol; C077793:candesartan cilexetil