EFFECTS OF DESETHYLAMIODARONE ON THE ELECTROCARDIOGRAM IN CONSCIOUS FREELY MOVING ANIMALS - PHARMACOKINETIC AND PHARMACODYNAMIC MODELING USING COMPUTER-ASSISTED RADIO TELEMETRY

Desethylamiodarone (DEA), the major active metabolite of amiodarone (A MD), plays a significant role in the electrophysiological effects obse rved during AMD therapy. The pharmacokinetics and pharmacodynamics of DEA were studied in rats. Animals were administered DEA (20 or 40 mg k g(-1)) and blood samples were collected. The heart rate, PQ, QR, QS, Q T, RR intervals, and P, R, S, and T amplitudes were also measured afte r dosing using telemetry. DEA followed a biexponential decline with a t(1/2 beta) of 54.8 and 46.2 h after the 20 and 40 mg kg(-1) doses, re spectively. The relationship between DEA and the QT interval or T ampl itude was best described by a sigmoid E(max) model. The mean (+/- SD) E(max) for QT and T amplitude was 32.23 (+/- 2.47)% and 0.12 (+/- 00.9 ) mV, respectively. The mean (+/- SD) EC(50) value was 297.5 (+/- 22.8 0) ng ml(-1) for QT and 139.8 (+/- 28.69) ng mL(-1) for the T amplitud e. The electrophysiological changes observed with DEA are similar to t hose with AMD. These results further support the contribution of DEA t o the efficacy noted during AMD therapy and provide and viable animal for continued description of this relationship.