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Letter to the Editor
Dear Sir,
The letter by Mullier
1
in response to our article titled ‘The grapefruit:
an old wine in a new glass? Metabolic and cardiovascular
perspectives’
2
refers. The author states that amiodarone is not
only a prodrug but also has inherent pharmacodynamic effects,
just like its metabolite N-desethyamiodarone (N-DEA), which he
correctly suggests could have even greater pharmacological effects
than the parent compound. However, we need to emphasise that
even though N-DEA has similar class III anti-arrythmic effects, it
has faster sodium channel blockade and lower class IV effects than
amiodarone.
3-8
The inhibition of pre-hepatic/hepatic metabolism of amiodarone
by CYP3A4 alters both plasma and cardiac substrate:metabolite
ratios. It therefore reduces alterations of PR and QTC intervals,
9
and hence diminishes the anti-arrythmic effects of amiodarone.
Both amiodarone and N-DEA have long half-lives (50 and 60 days,
respectively),
10-12
and at normal therapeutic doses, the relative
contribution of either to the anti-arrythmic and overall cardiac
electrophysiological effects is not presently known, despite the
aforementioned interaction with grapefruit juice. This, however,
does not disqualify amiodarone as a prodrug.
The interaction of grapefruit juice with amiodarone is more
complicated than previously thought. Naringenin, the naringin (the
predominant flavonoid in grapefruit juice) aglycone, has recently
been reported to prolong QTC by inhibiting the rapid component
of delayed rectifier K+ current (Ikr), leading to significant QT
prolongation in healthy subjects and in patients with dilated
or hypertensive cardiomyopathy,
13
as well as in experimental
conditions.
14
It is therefore envisaged that the pro-arrythmic actions
of naringin or grapefruit juice, just like all class III anti-arrythmic
agents, may put patients with myocardial structural disorders at risk
of provoking torsades des pointes.
Even though cases of QT prolongation and torsades de pointes
with amiodarone are rare, a case has been reported of a female
patient who presented with marked QT prolongation associated
with ventricular arrhythmias including torsades de pointes, requiring
electrical cardioversion after amiodarone administration, after she
had been drinking large quantities of grapefruit juice,
15
among
others. Perhaps we should have included these references in our
previous article to emphasise the fact that the interaction between
grapefruit juice and amiodarone is more elaborate than previously
thought. We thank the author for pointing out the typing errors in
our references.
PMO Owira
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