Different stereoselective effects of (R)- and (S)-propafenone: Clinical pharmacologic, electrophysiologic, and radioligand binding studies

Abstract

Propafenone is a class 1c antiarrhythmic agent with moderate beta-blocking activity as a result of a structural similarity to beta-adrenoceptor antagonists. In a randomized, double-blind crossover exercise study, eight healthy volunteers were examined before and 2 1/2 hours after oral administration of 300 mg (R,S)-, 150 mg (R)-, and 150 mg (S)-propafenone hydrochloride. The mean rate pressure product was significantly reduced by (R,S)-propafenone hydrochloride (-5.2%; p = 0.045) and half-dosed (S)-propafenone hydrochloride (-5.9%; p = 0.013), whereas the (R)-enantiomer caused no significant changes. There was a significant difference between the effects of (R)- and (S)-propafenone (p = 0.033). In beta-adrenoceptor-binding inhibition experiments with (S)-(125I)iodocyanopindolol in a sarcolemma-enriched cardiac membrane preparation, the eudismic ratio of (S)- over (R)-propafenone was 54. On the spontaneously beating Langendorff-perfused guinea pig heart, 3 x 10(-6) mol/L of both (R)- and (S)-propafenone resulted in significant changes (p less than 0.01) on His bundle conduction (+79% +/- 27% and +69% +/- 9%), as well as comparable decreases in the maximal rate of pacing with 1:1 conduction of the atrial (-54% +/- 10% and -57% +/- 8%) and ventricular myocardium (-42% +/- 6% and -43% +/- 6%), indicating equal effects in sodium channel-dependent antiarrhythmic class 1 activity. Thus (R)- and (S)-propafenone exert different beta-blocking actions but equal effects on the sodium channel-dependent antiarrhythmic class 1 activity. More specific antiarrhythmic class 1 therapy with reduction of beta-blocking side effects may be attained with optically pure (R)-propafenone hydrochloride instead of the currently used racemic mixture.

Enantioselective plasma protein binding of propafenone: Mechanism, drug interaction, and species difference

“…Although both enantiomers are equally potent in their activity as sodium channel blockers, the (S)-enantiomer exhibits b-blocking activity $100 times higher. 1 Besides, (R)-PPF is cleared faster than (S)-PPF after administration of racemic PPF to healthy volunteers. 2 It has been thought that besides stereoselective metabolism, stereoselective protein binding might be also responsible for the differences in pharmacokinetics between PPF enantiomers.…”

Direct enantiomeric high performance liquid chromatographic separation of propafenone and its major metabolite in serum on a cellulose tris‐3,5‐dimethylphenyl carbamate chiral stationary phase

“…(1989) concluded that the administration of optically pure (R)-PRO might be of advantage in patients intolerant to p-blockade, although their study lacks sufficient evidence of the @-blocking effects of (S)-PRO in humans. Recently, Stoschitzky et al (1990) substantiated the concept of administering optically pure (R)-PRO in order to achieve more specific antiarrhythmic class l c therapy with less p-blocking side-effects instead of the currently used racemic mixture. However, when additional @-blockade is needed, it could be attained by co-administration of such pure (3-adrenoceptor antagonists such as atenolol or propranolol.…”

Electrophysiological properties of the propafenone-analogue GE 68 (1-[3-(phenylethyl)-2-benzofuryl]-2-(propylamino)-ethanol) in isolated preparations and ventricular myocytes of guinea-pig hearts

“…Racemic propafenone is classified as 1C antiarrhythmic agent (Kohlhardt and Seifert 1980;Dukes et al 1984;Tamargo and Delgado 1985;Bryson et al 1993) with a weak calcium antagonistic effect (Ledda et al 1981;Dukes et al 1984;Delgado et al 1991), and a non-selective b-adrenoceptor blocking activity (Ledda et al 1981;Dukes et al 1984;Delgado et al 1985;Groschner et al 1991) which may be clinically relevant in human (Funck-Brentano et al 1990;Stoschitzky et al 1990;Malfatto et al 1993;Kroemer et al 1994), especially in poor metabolizers (Barbey 1991). The (+)-S-enantiomer is the b-adrenoceptor blocking moiety of propafenone (Kroemer et al 1989;Stoschitzky et al 1990;Groschner et al 1991). However, both (R)-and (S)-propafenone exert equal class I antiarrhythmic activity (Stoschitzky et al 1990;Groschner et al 1991;Schreibmayer and Lindner 1992).…”

“…The (+)-S-enantiomer is the b-adrenoceptor blocking moiety of propafenone (Kroemer et al 1989;Stoschitzky et al 1990;Groschner et al 1991). However, both (R)-and (S)-propafenone exert equal class I antiarrhythmic activity (Stoschitzky et al 1990;Groschner et al 1991;Schreibmayer and Lindner 1992). Thus, more specific antiarrhythmic class I therapy with reduction of b-blocking side effects may be attained with optically pure (R)-propafenone hydrochloride instead of the currently used racemic mixture.…”