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Letter to the editor

Editor, I wish to comment on the article 'Erythromycin and terfenadine should not be used together' (Aust Prescr 1995;18:18) by Associate Professor R. Moulds. It is well known and documented that an interaction can occur between erythromycin and terfenadine. However, more than 99% of terfenadine is converted to its carboxylic acid metabolite and other active metabolites via the cytochrome P450 system on first pass through the liver. However, when erythromycin is administered, there is competition for the isoenzyme resulting in raised levels of the parent compound terfenadine.

There is a relationship between the observed increase in QT interval and the circulating level of terfenadine, but little or no relationship with levels of the acid metabolite. The impression given by Professor Moulds' article is that the metabolite is potentially cardiotoxic. All data currently available point to the metabolite being devoid of cardiotoxic effects. In individuals who are using Teldane at the recommended dose, the parent compound is essentially undetectable in plasma, due to the extensive first pass metabolism. The metabolite is responsible for the antihistamine activity. According to the article, the metabolite has been implicated in causing arrhythmias and in the development of torsades de pointes, which is incorrect.

In the interest of concerned practitioners, I wish to have this error corrected.

Errol Kaplan
Associate Medical Director
Marion Merrell Dow Australia Pty Ltd
Frenchs Forest, N.S.W.


Author's comments

Associate Professor R.F.W. Moulds, the author of the article, comments:

Dr Kaplan is correct that the most recent evidence, whilst not absolutely conclusive, suggests that it is the native terfenadine, rather than the active metabolite, which is responsible for the potentially fatal arrhythmias documented when erythromycin is coadministered with terfenadine.

My report was based on studies which showed that the concentration of the metabolite increased markedly when terfenadine was administered to normal volunteers in the presence of erythromycin, and the accumulation of the metabolite was associated with ECG changes thought to
be a marker for the development of more severe arrhythmias.

However, more recent information, including in vitro testing of terfenadine and its metabolite on isolated cardiac cells, suggests it is more likely to be increased concentrations of terfenadine itself, caused by delayed conversion of terfenadine to its metabolite, rather than the accumulation of the metabolite, which is responsible for the arrhythmias.

As a separate issue, it should also be noted that large doses of erythromycin can themselves cause cardiac arrhythmias, so it is possible that the arrhythmias caused by the combination of terfenadine and erythromycin have a multi factorial basis.

Errol Kaplan

Associate Medical Director, Marion Merrell Dow Australia Pty Ltd, Frenchs Forest, N.S.W.

R.F.W. Moulds

Department of Clinical Pharmacology and Therapeutics, Royal Melbourne Hospital, Melbourne