Stereoselective disposition and pharmacologic activity of propafenone enantiomers.

Abstract

Propafenone is an antiarrhythmic drug that produces a variable degree of P3-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 p3-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 SIR 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 1-adrenoceptor was approximately 100-fold greater for (+)-S-propafenone (K, 7.2±2.9 nM) than for the (-)-R-enantiomer (K;, 571±141 nM). We conclude that during relation has been reported. One explanation for this variability is the genetically determined impairment in approximately 7% of the Caucasian population to metabolize propafenone.1 This polymorphism cosegregates with the ability to 4-hydroxylate the antihypertensive debrisoquine and correlates with the functional presence or absence of the hepatic cytochrome P-450db1.6 Patients with the extensive metabolizer phenotype (EM) or the poor metabolizer phenotype (PM) can be distinguished,' and the metabolic pathway affected by polymorphic oxidation is the formation of the active metabolite 5-hydroxy propafenone.7,8 Propafenone is administered as a racemic mixture of (+)-S-and (-)-R-enantiomers. Pharmacokinetic differences between the enantiomers of other racemic drugs, such as metoprolol and N-propylajmaline, which are substrates for P-450db1, have been found in EM but not in PM subjects, indicating the potential for stereoselective metabolism of substrates for this cytochrome P 450.9, 1 The in vitro electrophys-

The effects of the stereoisomers of propafenone and diprafenone in guinea‐pig heart

“…Irrespective of dextro-or laevorotatory properties, resolved enantiomers with (S)-configuration, as determined chromatographically and by CD-spectroscopy, exerted considerably higher fi-adrenoceptor affinity than their corresponding (R)-enantiomers. A similar pattern of stereoselectivity has recently been reported for the binding of propafenone to human lymphocyte JJ-adrenoceptors (Kroemer et al, 1989). In the present experiments, enantiomeric affinity ratios of 1.2-1.8 log units were obtained.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…This lipophilic, high-clearance drug is subject to variable first-pass metabolism and nonlinear pharmacokinetics (Siddoway et al, 1987;Capucci et al, 1990). Its enantiomers have equal sodium channel blocking activity (the primary effect), but S-propafenone is 100-fold more potent as a ␤-blocker (Kroemer et al, 1989a). Propafenone is metabolized via CYP2D6 to 5-hydroxypropafenone, which has sodium channel blocking activity similar to that of the racemic parent drug but less ␤-blockade (Kroemer et al, 1989b), and also by CYP1A2 and 3A4 to N-desalkylpropafenone (some, but less, activity) (Botsch et al, 1993).…”

“…The propafenone/ 5-hydroxypropafenone ratio correlates with the debrisoquine metabolic ratio . PMs have 3-to 7-fold higher propafenone AUCs at steady state than EMs and produce very low or negligible concentrations of 5-hydroxypropafenone (Siddoway et al, 1987;Kroemer et al, 1989a;Lee et al, 1990;Dilger et al, 1999;Labbe et al, 2000). CYP2D6 status is generally thought to matter little for antiarrhythmic effect (Siddoway et al, 1987;Labbe et al, 2000), although some studies have suggested greater efficacy in those with reduced CYP2D6 activity (Jazwinska-Tamawska et al, 2001;Cai et al, 2002).…”

Which Metabolites Circulate?

“…On the basis of the conceptual framework discussed in Theoretical Considerations of Determining In Vivo Metabolite Exposure, this was ascribed to either a low CL f and/ or a high CL m for the metabolite. For instance, low circulating concentrations of N-desalkyl metabolites of azimilide (Riley et al, 2005), elzasonan (Kamel et al, 2010), imatinib (Gschwind et al, 2005), itraconazole (Isoherranen et al, 2004), olanzapine (Kassahun et al, 1997), propafenone (Kroemer et al, 1989), and repaglinide (van Heiningen et al, 1999) can be attributed to the relatively minor contribution of N-dealkylation to the overall clearance of these drugs. On the other hand, low circulating concentrations of mchlorophenylpiperazine (Fig.…”