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Clinical Pharmacokinetics of Levorotatory and Racemic Disopyramide, at Steady State, Following Oral Administration in Patients with Ventricular Arrhythmias
Author(s) -
Corre Pascal,
Gibassier Denis,
Descaves Christian,
Sado Pierre,
Daubert Jean Claude,
Verge Roger
Publication year - 1989
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1989.tb03284.x
Subject(s) - disopyramide , pharmacokinetics , chemistry , crossover study , enantiomer , racemic mixture , stereoselectivity , oral administration , first pass effect , steady state (chemistry) , pr interval , pharmacology , medicine , stereochemistry , heart rate , biochemistry , alternative medicine , pathology , blood pressure , placebo , catalysis
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 crossover 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 < .01), and QTc interval (+9.2% and +7%, respectively, P < .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 < .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.