Steady-state plasma concentrations of propafenone--chirality and metabolism.
In a selected group of 86 patients (60 males, 26 females) with symptomatic ventricular arrhythmias, possible interactions between metabolic and chiral effects at steady-state were investigated by comparing the plasma levels of propafenone, its major metabolites and the 2 structural isomers. The antiarrhythmic drug propafenone is metabolized--besides a minor dealkylation pathway--mainly via 5-hydroxylation. It is a well-known phenomenon that this oxidative pathway is not shared by all individuals to the same extent. We were able to verify among our subjects the portion of so-called poor metabolizers reported in the literature for the total population. Propafenone was administered as a slow release formulation at 3 different dose regimens (2 x 225 mg, 2 x 325 mg and 2 x 425 mg). The crude drug is a racemic mixture of equal amounts of R- and S-forms. During treatment, the plasma S and R ratio was shifted towards the S-isomer due to preferential clearance of the R-form. It was further found that neither a genetic disposition (gender, metabolic phenotype) nor age or the dose applied had any influence on the measured plasma isomer ratio.
Max Planck Institute for Physiological and Clinical Research, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany.
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M
Volz
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V
Mitrovic
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M
Schlepper
D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011405:Propafenone / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D013237:Stereoisomerism
D003692:Delayed-Action Preparations; D011405:Propafenone