Stereoselective disposition and pharmacologic activity of propafenone enantiomers.
Propafenone is an antiarrhythmic drug that produces a variable degree of beta-blockade in humans and is administered as a racemate. To examine the relative contribution of the individual enantiomers to pharmacologic effects seen during treatment with propafenone, we assessed the steady-state plasma concentrations of (+)-S-propafenone and (-)-R-propafenone in seven patients who were on long-term oral therapy, and we evaluated the electrophysiologic and beta-blocking properties of both enantiomers in vitro. The metabolism of propafenone is known to be polymorphic and to cosegregate with that of debrisoquine-4-hydroxylation. Among five patients with the extensive metabolizer phenotype (EM), the ratio of the area under the plasma concentration-time curve of (+)-S-propafenone to (-)-R-propafenone was 1.73 +/- 0.15 (mean +/- SD). In the other two patients, who had the poor metabolizer phenotype (PM), the concentrations of both enantiomers were elevated but the S/R ratios were similar to those seen in patients with EM. In canine cardiac Purkinje fibers, both enantiomers produced similar frequency-dependent depression of maximum upstroke of phase 0. In contrast, the affinity of the human lymphocyte beta 2-adrenoceptor was approximately 100-fold greater for (+)-S-propafenone (Ki, 7.2 +/- 2.9 nM) than for the (-)-R-enantiomer (Ki, 571 +/- 141 nM). We conclude that during long-term oral therapy, propafenone undergoes stereoselective disposition in patients with either EM or PM. beta-Blockade during propafenone therapy is likely related to accumulation of (+)-S-propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)
Kroemer
H K
HK
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232.
Funck-Brentano
C
C
Silberstein
D J
DJ
Wood
A J
AJ
Eichelbaum
M
M
Woosley
R L
RL
Roden
D M
DM
D000328:Adult; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004594:Electrophysiology; D006801:Humans; D008297:Male; D010641:Phenotype; D011405:Propafenone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011405:Propafenone