Potent electrophysiologic effects of the major metabolites of propafenone in canine Purkinje fibers.
Marked interindividual variability has been reported in the plasma concentrations of the antiarrhythmic agent propafenone required for arrhythmia suppression. One possible explanation is the variable generation of active metabolites: it is known that the major metabolite 5-hydroxypropafenone and the more recently described metabolite N-depropylpropafenone can accumulate in plasma to concentrations similar to those of propafenone, and 5-hydroxypropafenone has proven active in animal models. We therefore compared the effects of these metabolites to those of propafenone on action potential characteristics of canine Purkinje fibers at a wide range of cycle lengths. After base-line measurements, propafenone or 5-hydroxypropafenone was superfused at successive concentrations of 0.1, 0.3 and 1.0 microM for 30 min each and measurements were repeated. Both drugs depressed maximum phase zero upstroke slope of the action potential (Vmax); 5-hydroxypropafenone was similar to propafenone in potency with both causing significant effects at very low concentrations (0.1 microM). Vmax depression was cycle length-dependent and the time constants for onset of and recovery from use-dependent Vmax depression were similar. The compounds also shortened action potential duration at 50% but not 90% repolarization. N-depropylpropafenone produced electrophysiologic effects that were similar to those of propafenone and 5-hydroxypropafenone but was less active. We conclude that these metabolites are sufficiently potent that they may explain at least in part the unpredictable concentration-response relationship seen with propafenone.
Thompson
K A
KA
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
Iansmith
D H
DH
Siddoway
L A
LA
Woosley
R L
RL
Roden
D M
DM
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001711:Biotransformation; D004285:Dogs; D006329:Heart Conduction System / Q000187:drug effects*; D066298:In Vitro Techniques; D011405:Propafenone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology
D011405:Propafenone; C044307:5-hydroxypropafenone; C045806:N-depropylpropafenone