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REVIEW

SA JOURNAL OF DIABETES & VASCULAR DISEASE

50

VOLUME 12 NUMBER 2 • NOVEMBER 2015

by atherogenic levels of native LDLs: Balance between transcriptional and post

transcriptional regulation.

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et al.

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treatment on the electronegative low-density lipoprotein present in patients with

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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

References

1.

Mullier FO. The grapefruit: an old wine in a new glass.

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Owira PMO, Ojewole JAO. The grapefruit: an old wine in a new glass.

Cardiovasc

J Afr

2010;

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: 280–285.

3.

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patient.

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4.

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induction.

J Am Coll Cardiol

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5.

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et al.

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J Am Coll Cardiol

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6.

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et al

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J Am Coll Cardiol

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7.

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the dog.

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drug concentrations.

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9.

Libersa CC, Brique SA, Mote KB,

et al

. Dramatic inhibition of amiodarone

metabolism induced by grapefruit juice.

Br J Clin Pharmacol

2000;

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10. Harris L, Mckenna W, Rowland DE,

et al

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desethylamiodarone levels in chronic oral therapy.

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therapy.

Biopharm Drug Dispos

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13. Piccirillo G, Magri D, Matera S,

et al

. Effects of pink grapefruit juice on QT

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subjects.

Translational Res

2008;

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14. Lin C, Ke X, Ranade V, Somberg J. The additive effects of active component

of grapefruit juice (naringenin) and antiarrythmic drugs on HERG inhibition.

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15. Agosti S, Casalino L, Bertero G. A dangerous fruit juice.

Am J Emergency Med

2012;

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