Cardiotoxic interaction of metabolites from a prodrug segment cilexetil (cyclohexyloxy-carbonyloxy-ethyl) with digoxin in the canine failing heart.

Potential risks of cyclohexanol (CH) and cyclohexanediol (CHD) isomers, which are the metabolites derived from cilexetil ester side-chain of several prodrugs such as antibiotics (e.g. cefotiam hexetil) and an antihypertensive agent (candesartan cilexetil), were examined in beagles that were made congestive heart failure (CHF) by rapid ventricular pacing. The following three experiments tested the cardiac effects of i.v. doses of: (1) the metabolites alone, (2) the metabolites under the digoxin-induced bradycardia, and (3) the metabolites given concomitantly with digoxin (0.02 mg kg(-1)). Experiment 1: t-1,2- or 1,4-CHD alone (0.1-12 mg kg(-1)) exerted transient yet reproducible supraventricular or ventricular arrhythmia dose-dependently, whereas CH and 1,3-CHD at 12 mg kg(-1) showed no cardiac effect at all. Experiment 2: t-1,2-CHD (0.1-4 mg kg(-1)), but not CH or 1,3-CHD, induced the additive arrhythmia dose-dependently; t-1,2-CHD (12 mg kg(-1)) caused frequent premature supraventricular contractions and/or irreversible paroxysmal supraventricular tachycardia. Experiment 3: t-1,2-CHD, not CH or 1,3-CHD, caused fatal arrhythmia: one dog showed torsade de pointes followed by ventricular fibrillation, while another showed 3rd degree atrioventricular block and eventually cardiac arrest. In both Experiments 2 and 3, saline vehicle added onto digoxin never caused the irreversible, fatal arrhythmia. In a separate study using healthy dogs without CHF, none of these metabolites did produce cardiac effect. Given the potential risk of generating cardiotoxic metabolites from cilexetil-bearing prodrugs, the use of such prodrugs should be avoided from the patients with CHF, particularly from those who are receiving cardiac glycosides.