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Stereoselective glucuronidation of propafenone and its beta-blocker analogues by human recombinant UGT1A3 and UGT1A9 from the recombinant baculovirus in insect sf9 cells was studied. The glucuronides produced in incubation mixtures were assayed by HPLC equipped with UV detector, and identified by beta-glucuronidase. The stereoselective glucuronidation was measured by pre-column 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocynate (GITC) derivatization HPLC method for propafenone and esomolol. In all of ten beta-blocker drugs studied, six showed the glucuronidation activity with UGT1A9, while four with UGT1A3. From roughly quantitative stereoselective glucuronidation study of racemic beta-blocker analogues by UGT1A9, propranolol had a high ratio of the ratios of S- to R-isomer glucuronide (S-G/R-G), about 4.3, the ratios of terbutaline, atenolol and esomolol were 3.3, 3.1 and 2.8 respectively, sotalol and propafenone were 2.3 and 2.0. In a word, S-isomers of these drugs were glucuronidated by human UGT1A9 much faster than their antipodes.

beta-receptor blockers--atenolol, celiprolol, metoprolol, propafenone, propranolol and talinolol--extracted from plasma, were separated by TLC method on silica gel by ascending technique. Isolation of drugs was performed by using liquid-liquid extraction after alkalization of blood plasma. Suitable conditions for separation were established using ethyl acetate-acetone-ammonia (5:4:1) as the mobile phase. The substances were identified by UV irradiation (254 nm) or by reactions with a variety of reagents. The visual limits of determination of named beta-blockers, after reaction with indicators, are between 100-300 ng; celiprolol and talinolol are the most sensitively detectable of investigated substances.

Background: Therapy with racemic compounds produces effects that can be attributed to both (S)- and (R)-enantiomers. Here we have tested the hypothesis that an enantiomer-enantiomer interaction would modulate the effects of treatment with a racemate, the antiarrhythmic propafenone. Previous studies have shown that while the enantiomers of propafenone exert similar sodium channel-blocking (QRS widening) effects, it is the (S)-enantiomer that produces beta-blockade; moreover, we have demonstrated recently that (R)-propafenone inhibits the metabolism of (S)-propafenone in vitro., Methods and Results: This single-blind, randomized study compared the effects of (R/S)-, (S)-, (R)-propafenone (150 mg q 6 hours for 4 days) and placebo on QRS duration (delta QRS) and on maximum exercise heart rate (delta HRmax), an index of beta-blockade. The clearance of (S)-propafenone was significantly lower (-55 +/- 24%, P < .001) during treatment with (R/S)-propafenone than with the (S)-enantiomer alone, and delta HRmax was significantly altered during (R/S)-propafenone (-8.8 +/- 6.6 beats per minute; P < .01) and during (S)-propafenone (-4.3 +/- 4.8 beats per minute; P < .01) but not during (R)-propafenone (-1.8 +/- 6.4 beats per minute) or placebo (0.3 +/- 7.1 beats per minute). In contrast, (R/S)-, (S)-, and (R)-propafenone all prolonged QRS compared with placebo., Conclusions: These data indicate that (R)-propafenone impairs the disposition of (S)-propafenone in humans. As a result, the beta-blocking effects of 150 mg of racemic propafenone (75 mg of the [S]-enantiomer) were more pronounced than those of 150 mg of (S)-propafenone alone. Thus, the effects of racemic drug therapy are not necessarily those predicted by summation of the effects of the individual enantiomers.