title: Comparative pharmacokinetics and clinical pharmacology of propafenone enantiomers after oral administration to man.
abstract: The pharmacodynamic and pharmacokinetic behavior of (R)- and (S)-propafenone was investigated in a group of seven healthy volunteers, one of whom belonged to the phenotype of poor debrisoquine hydroxylators. Each volunteer received 250 mg of either enantiomer as a solution in randomized order with a washout period of one week in between. The pharmacodynamic evaluation comprised cardiovascular parameters (HR, PQ, QRS, QT, BP) and tolerability (self-assessment questionnaire, hematology, clinical chemistry). For pharmacokinetic purposes plasma levels of the parent compounds (R, S) and their 5-hydroxylated metabolites (5-R, 5-S) were measured. As expected, there was a small but distinct increase of PQ interval with a maximum 2 h after drug intake. No difference was observed between both enantiomers tested. In the poor hydroxylator prolongation of PQ interval was less compared to extensive metabolizers, though plasma concentrations of the unchanged drug were considerably higher. Inspection of the individual concentration time profiles in the other subjects provided additional evidence that the 5-OH-metabolite also contributes to this effect. Other ECG parameters, heart rate and blood pressure remained unaffected. Both enantiomers were well tolerated: no drug-related side effects concerning general well-being and laboratory parameters were observed. In contrast to pharmacodynamic effects (on ECG) a distinct enantioselectivity of metabolic and/or distributive processes can be observed in the group of efficient hydroxylators manifesting itself in a lower clearance for R (ratio 0.50 +/- 0.19, probability of error less than 1%), in spite of a higher terminal elimination rate constant (ratio 1.64 +/- 0.63, probability of error less than 10%). This difference cannot be accounted for by the different degrees of protein binding of the enantiomers (fu(R) = 0.076; fu(S) = 0.049). The experience obtained with one poor hydroxylator seems to indicate that enantioselectivity in terms of oral clearance Cl/F might be lost in this phenotype. The distinctly lower clearance values for the poor hydroxylator when compared to the corresponding data for efficient hydroxylators, seem to be the reflection of the lower metabolic capacity of this phenotype.
authors.affiliation: Knoll AG, Dept. Biochemistry, Ludwigshafen/Rhein, FRG.
authors.forename: E
authors.initials: E
authors.lastname: Brode
authors.forename: H
authors.initials: H
authors.lastname: Müller-Peltzer
authors.forename: M
authors.initials: M
authors.lastname: Hollmann
mesh_terms: D000328:Adult; D004562:Electrocardiography; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011405:Propafenone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D011405:Propafenone