Stereoselectivity in Proarrhythmic Potential

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Chapter: Pharmacovigilance: Withdrawal of Terodiline: A Tale of Two Toxicities

Stereoselective interactions at receptors and ion channels are well known in the activities of β-blockers and dihydropyridine calcium channel blockers.


STEREOSELECTIVITY IN PROARRHYTHMIC POTENTIAL

Stereoselective interactions at receptors and ion channels are well known in the activities of β-blockers and dihydropyridine calcium channel blockers. Similar stereoselective interactions at potassium channels have also been described with enantiomers of drugs such as (+) -(R)-bupivacaine, (+) -(R)-halofantrine and (−) -(4S,6S)-acetylmethadol (levacetylmethadol). As regards their adverse pharmacodynamic effects on the heart, both prenylamine and terodiline display stereoselectivity (Rodenkirchen, Bayer and Mannhold, 1980; Bayer, Schwarzmaier and Pernice, 1988; Hartigan-Go et al., 1996).

Although a number of currents, predominantly mediated by potassium ions, are involved during repolarization, the one almost universally affected by all the drugs (non-cardiovascular and non-antiarrhythmics alike) that prolong the QT interval and induce torsade de pointes is the rapid component of the delayed rectifier potassium channel, known as the IKr current. At a molecular level, the native IKr chan-nel is a co-assembly of hERG (human ether-a-go-go related gene) β-subunits and MiRP1 β-subunits. The hERG channel is the target of almost every QT-prolonging drug. Although prenylamine and terodiline have both been shown now to block either the hERG or the IKr channel (Jones et al., 1998; Katchman et al., 2006), there are no published reports of in vitro studies investigating the activity of individual enantiomers of these drugs on either of these targets. Interestingly, however, tolterodine (a structural analogue of terodi-line) is marketed as the (+) -(R)-enantiomer, and has recently been shown in in vitro studies to block the hERG cardiac ion channel (Kang et al., 2004).

As discussed earlier, the overall data suggest that the proarrhythmic effect of prenylamine in man is most likely mediated by (+) -(S)-prenylamine, as demonstrated by studies on action potential dura-tion (Bayer, Schawrzmaier and Pernice, 1988). This conclusion must be seen in the context of the observa-tions that although the maximum plasma concentra-tion and AUC of the (+) -(S)-enantiomer are normally 4–5 times lower than those of the (−) -(R)-enantiomer, the reverse may be the case in PMs of CYP2D6, since the data suggest that this CYP isoform most prob-ably mediates the metabolic elimination of (+) -(S)-prenylamine. Due to its longer elimination half-life, -(S)-prenylamine would accumulate in the PMs. Not surprisingly, most patients with prenylamine-induced proarrhythmias were also receiving doses in the lower range of the recommended schedule. A number of drugs such as quinidine only induce torsade de pointes at low concentrations because other elec-trophysiological effects supervene at higher concen-trations. As far as the author is aware, there are no published reports of in vitro studies investigating the activity of individual enantiomers of terodiline on action potential duration.

There are no in vivo data on stereoselective cardiac effects of prenylamine, or on the concentrations of the two enantiomers in patients during episodes of prenylamine-induced proarrhythmias. However, in vivo studies in nine healthy volunteers have shown conclusively that the proarrhythmic poten-tial of terodiline resides exclusively in its (+) -(R)-enantiomer (Hartigan-Go et al., 1996). Peak effects occur 8 hours after dosing, when mean increases in the QTc interval from baseline were 3 ms after the placebo, 23 ms after 200 mg racemic terodiline, 19 ms after 100 mg (+) -(R)-terodiline and 0 ms after 100 mg -(S)-terodiline. Although there were differences in the pharmacokinetics of the two enantiomers, these were not sufficient to account for the differences in ECG effects, and at these high doses, their elimination half-lives were similar. In the two genotypic PMs of CYP2D6, the half-lives of (+) -(R)-terodiline ranked 7th and 8th and those of -(S)-terodiline 4th and 9th in order. It will be recalled, however, that at clinical doses, (+) -(R)-terodiline predominates in the plasma and could accumulate further in PMs of CYP2D6.

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