Clinical pharmacokinetics of levorotatory and racemic disopyramide, at steady state, following oral administration in patients with ventricular arrhythmias.
Electrophysiological effects, antiarrhythmic activity and kinetics of levorotatory disopyramide (R(-) DP) and racemic disopyramide (equimolar mixture of R(-) DP and S(+) DP) were compared in patients with ventricular arrhythmias. This double blind cross-over randomized trial was achieved, at steady-state, following oral administration of 200 mg three times a day. In comparison with baseline values, electrophysiological data indicated that R(-) DP and racemic DP prolonged, significantly and similarly, PR interval (+11.7% and +10%, respectively, P less than .01), and QTc interval (+9.2% and +7%, respectively, P less than .001), while QRS interval was not significantly affected. The antiarrhythmic activity, assessed by percent reduction in ventricular extrasystoles frequency, showed a similar efficiency of levorotatory and racemic DP: 80% and 74%, respectively (P = .24). Ventricular tachycardias disappeared with both treatments in the three patients concerned. During the racemic period, the mean total plasma clearance, expressed as CL/F, of S(+) DP (114.6 ml/min), was significantly lower than that of R(-) DP (157 ml/min), (P less than .001). The mean total plasma clearance of R(-) DP, during the levorotatory period (163 ml/min), did not differ from the respective value determined during the racemic period (P = .32). During the racemic period, the stereoselective difference in total plasma clearances, which is not observed when DP enantiomers are administered separately, may result from an increase in unbound fraction of R(-) DP, due to the presence of S(+) DP, which is known to be a potent displacer of R(-) DP.
Le Corre
P
P
Laboratoire de Pharmacie Galénique et Biopharmacie, Université de Rennes, France.
Gibassier
D
D
Descaves
C
C
Sado
P
P
Daubert
J C
JC
Le Verge
R
R
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D005117:Cardiac Complexes, Premature / Q000188:drug therapy* / Q000378:metabolism; D004206:Disopyramide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D006352:Heart Ventricles; D006801:Humans; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D013237:Stereoisomerism; D013610:Tachycardia / Q000188:drug therapy* / Q000378:metabolism
D004206:Disopyramide