Comparative electrophysiological effects of propafenone, 5-hydroxy-propafenone, and N-depropylpropafenone on guinea pig ventricular muscle fibers.
Propafenone (Pf) is a class I antiarrhythmic drug that can be given both orally and intravenously. In order to examine whether its two major metabolites [5-hydroxypropafenone (5-OH-Pf) and N-depropylpropafenone (N-DP-Pf)] possess pharmacodynamical properties, we compared their electrophysiological effects to those of the parent drug on papillary muscle fibers from guinea pig ventricular myocardium. After baseline action potential and refractory period characteristics were measured at different pacing rates, the tissue preparations were superfused with either Pf, 5-OH-Pf, or N-DP-Pf at five different concentrations and electrophysiological characteristics were studied again. The maximal rate of depolarization (Vmax) was depressed by the three compounds only at the highest concentration, although the effect of N-DP-Pf was slightly less than the other two. Refractory periods were altered only by the highest concentration of 5-OH-Pf. Propafenone and N-DP-Pf exhibited equally slow on-set/off-set kinetics of the sodium channel block, whereas those of 5-OH-Pf were twice as long, which seems to suggest a slower rate of dissociation of the latter from the inactivated sodium channels. Thus, 5-OH-Pf and N-DP-Pf comply with the definition of the class IC antiarrhythmic drugs. The cumulative in vivo effects of the two metabolites and of the parent drug could have far reaching clinical implications, especially in the genetically predisposed extensive metabolizing subject.
Rouet
R
R
Hospital Pharmacology Laboratory, Faculté de Médecine, Lille, France.
Libersa
C C
CC
Broly
F
F
Caron
J F
JF
Adamantidis
M M
MM
Honore
E
E
Wajman
A
A
Dupuis
B A
BA
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010210:Papillary Muscles / Q000166:cytology / Q000187:drug effects; D011405:Propafenone / Q000031:analogs & derivatives* / Q000494:pharmacology*
D011405:Propafenone; C044307:5-hydroxypropafenone; C045806:N-depropylpropafenone