Cytochrome P450 drug interactions

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Editor, – We are writing with respect to the article 'Cytochrome P450 drug interactions: are they clinically relevant?' by J. Martin and M. Fay (Aust Prescr 2001;24:10-2). In this article, the authors state 'Some selective serotonin reuptake inhibitors (SSRIs) (e.g. fluoxetine, paroxetine and fluvoxamine) inhibit CYP2D6... The addition of fluoxetine, paroxetine or fluvoxamine (CYP2D6 inhibitors)...'. These statements are not accurate in that fluvoxamine maleate has, to date, not been shown to be a significant inhibitor of CYP2D6 - in vitro or clinically.1-7 The product information clearly states that `Fluvoxamine has only a weak effect on CYP2D6, and it is therefore not likely that it will increase plasma concentrations of drugs metabolised by CYP2D6 to a clinically relevant effect'.

Pamela Noble
Manager, Scientific Affairs & Medical Marketing
Solvay Pharmaceuticals
Pymble, NSW

Dr J. Martin and Dr M. Fay, authors of 'Cytochrome P450 drug interactions: are they clinically relevant?', comment:

It is prudent to be aware of the safety issues when prescribing fluvoxamine with other drugs that are metabolised by the cytochrome P450 system. Fluvoxamine, however, has only a weak inhibitory effect on CYP2D6 and we agree with Solvay Pharmaceuticals that this is unlikely to be as clinically significant as fluvoxamine's other well-documented drug interactions.

Editor, – It may be useful for readers to have some additional information about psychotropic drugs and cytochrome P450 enzymes (Aust Prescr 2001;24:10-2).

Fluvoxamine seems not to significantly inhibit 2D6 as it has no effect on the O-demethylation ratio of dextromethorphan at a steady state dose of 100 mg/day. However, fluvoxamine potently inhibits cytochrome P450 1A2 and most patients treated with even low doses of 100 mg/day will reach population minimums for CYP1A2 activity (i.e. become poor metabolisers). Other potent inhibitors of 1A2 are mexiletine, lidocaine, and (weaker) tocainide, and also flavones - a class of dietary phytochemicals found at high concentrations in tofu.

Cytochrome P450 1A2 metabolises many structurally related psychotropic drugs - for instance all the quaternary tricyclic antidepressants (clomipramine, amitriptyline, doxepin, dothiepin, but not nortriptyline) and also many neuroleptics like clozapine, olanzapine, chlorpromazine and structurally related drugs. Their metabolism is also induced by cigarette smoking which may have significant clinical consequences.

Besides nefazodone, fluoxetine (via its metabolite norfluoxetine, which can have a half-life of up to 14 days) is also an inhibitor of cytochrome P450 3A4 and may thus, inter alia, inhibit ergotamine metabolism and precipitate ergotism.

It is incorrectly stated in the article that serotonin syndrome can be precipitated by combining tricyclic antidepressants and selective serotonin reuptake inhibitors.

Ken Gillman
Honorary Senior Lecturer
James Cook University
Psycho Tropical Research Unit
Townsville, Qld.

Dr J. Martin and Dr M. Fay, authors of 'Cytochrome P450 drug interactions: are they clinically relevant?', comment:

The letter from Dr Gillman gives some interesting information on potential cytochrome P450 interactions with psychotropic drugs. However our brief was to focus on clinically significant drug interactions only, and we tried to use only reports from the literature that indicated clinical significance. The aim of the article was to provide a few general rules to help clinicians identify potential drug interactions, rather than provide an exhaustive list.

However, there are several points in this letter which we would like to comment on. Firstly fluoxetine, although having an active and long half-life metabolite, is unlikely to have much clinically relevant inhibition of CYP3A4. The evidence comes from in vivostudies with terfenadine and midazolam (CYP3A4 substrates) which showed no increase in plasma concentrations of these with the addition of fluoxetine, and no change in cognitive state when added to midazolam. In vitro, fluoxetine has one hundred times less CYP3A4 inhibition than ketoconazole.

Secondly, serotonin syndrome can be precipitated by giving a selective serotonin reuptake inhibitor to a patient already on a tricyclic antidepressant. Concentrations of amitriptyline, clomipramine, imipramine and maprotoline have been shown to increase up to five fold with the addition of both fluoxetine and fluvoxamine. This is associated with anticholinergic, serotonergic and adrenergic adverse effects.

Editor, – In the article on cytochrome P450 drug interactions (Aust Prescr 2001;24:10-2) there is mention of the inductive capacity of St John's wort on the CYP3A4 enzyme. In view of the high first-pass effect on oestradiol and the intermediate effect on ethinyloestradiol, is it possible for pill failure, breakthrough bleeding and postmenopausal bleeding to occur when St John's wort is used by women on the oral contraceptive or hormone replacement therapy?

James Brodribb
Obstetrician and Gynaecologist

Dr J. Martin and Dr M. Fay, authors of 'Cytochrome P450 drug interactions: are they clinically relevant?', comment:

We agree with Dr Brodribb that there is likely to be quite a significant drug interaction with St John's wort (CYP3A4 inducer) and oestrogen/progesterone (CYP3A4 substrates) combinations. However, we were unable to find case reports of this in the literature, unlike the interactions with St John's wort and other 3A4 substrates. However, because of the likelihood of a significant interaction we would discourage St John's wort from being used by patients taking the contraceptive pill or hormone replacement therapy. We would also encourage the reporting of any suspected drug interaction.