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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