Stereoselectivity In Proarrhythmic Potential

Stereoselectivity in the activity of ^-blockers and dihydropyridine calcium channel blockers at receptors and ion channels is well known. Stereo-selectivity in activity at potassium channels has also been described more recently for enantiomers of other drugs such as (+)-(R)-bupivacaine, (+)-(R)-halofantrine and (—)-(4S,6S)-acetylmethadol (levoacetylmethadol).

As regards their adverse secondary cardiac pharmacodynamics, both prenylamine and terodi-line display stereoselectivity (Rodenkirchen et al., 1980; Bayer et al., 1988; Hartigan-Go et al., 1996).

In cat papillary muscle preparations (Bayer et al., 1988), (+)-(S)-prenylamine exhibited a positive inotropic action over a wide concentration range, while the (—)-(R)-isomer had a negative inotropic effect. The positive inotropic effect of the (+)-(S)-isomer was particularly evident at low concentrations and at low stimulation rates. The maximum velocity of depolarisation was decreased by the (—)-(R)-isomer and somewhat increased by the (+ )-(S)-isomer and the racemic mixture at low concentrations. (+)-(S)-prenylamine prolonged the action potential plateau and the duration of total action potential and dysrrhythmia occurred in 4 of 12 isolated papillary muscle preparations. In contrast, (—)-(R)-isomer shortened the action potential duration to a minor extent. This effect was independent of stimulation rates but evident at low concentrations. Therefore, overall, the data suggest that the proarrhythmic effect of prenylamine in man may have been mediated by (+)-(S)-prenylamine. This finding must be seen in the context of the finding that although the maximum plasma concentration and AUC of the (—)-(R)-enantiomer exceed those of the (+)-(S)-enantiomer by 4- to 5-fold normally, the reverse may be the case in PMs of CYP2D6. This difference between the EMs and the PMs would be more evident at low doses. Not surprisingly, most patients with prenylamine-induced proar-rhythmias were receiving doses in the lower range of the recommended schedule.

As far as the author is aware, no in vitro study investigating the activity of individual enantiomers of terodilene on action potential duration has been reported to date. In vivo, however, the proar-rhythmic potential of terodiline has been shown to reside exclusively in (+)-(R)-terodiline. A doubleblind, placebo-controlled, randomised, crossover study in 9 healthy volunteers, given single oral doses of 200 mg racemic terodiline, 100 mg (+)-(R)-terodiline, 100 mg (—)-(S)-terodiline or placebo, revealed that both racemic and (+)-(R)-terodiline significantly increased the QT interval and the corrected QT interval (QTc). (—)-(S)-terodiline did not affect the QTc interval (Harti-gan-Go et al., 1996). Peak effects occurred 8 hours after dosing when mean increases in the QTc from baseline were —3 ms for the placebo, 23 ms for racemic terodiline, 19 ms for (+)-(R)-terodiline and 0 ms for (—)-(S)-terodiline. Although differences were observed between the pharmacokinetics of the two enantiomers, these were not sufficient to account for the differences in ECG effects, and their elimination half-lives (at these high doses) were similar. It will be recalled that (+ )-(R)-terodiline predominates at low concentration, is normally preferentially eliminated and could accumulate in PMs of CYP2D6.

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