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Ask the Mental Health Expert Archives 2001-2004

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Poor Metabolizer

Q. Are there any antidepressive medications that can be used by a poor metabolizer of the P-450 drugs? It appears that all of them utilize one or more of the subsets. What about MAO inhibitors? Are they metabolized by the P-450 isozymes?

A. As you may know, so-called poor or slow metabolizers have been found in as many as 4% of Black populations; 11% of the Caucasian population, and up to 21% of Oriental populations. The cytochome families studied have been mainly CYP 2C19 and CYP 2D6. Clearly, it is important to try to identify the specific CYP family that is impaired for the patient in question--something that could be done via a department of genetics or pharmacology at an academic medical center.

There is no reason why antidepressants can't be used in slow metabolizers--you just have to be very, very careful. Beginning with very small doses and measuring blood levels of the drug in question is appropriate. It is also important to avoid co-administration of other drugs metabolized by the same CYP enzyme. For example, if someone were a slow metabolizer in the CYP 2D6 system, one might begin with just 2 mg of fluoxetine (Prozac) rather than the usual 10 or 20 mg dose--then check a plasma fluoxetine level after a week or so, and again at steady-state.

Alternatively, one could select an antidepressant that has multiple routes of metabolism, on the assumption that the patient will not be a poor metabolizer in all of them. For example, citalopram is metabolized by CYP 3A4, 2C19, and 2D6. Mirtazepine also goes through multiple enzyme systems (CYP 1A2, 2D6, and 3A4). With respect to the MAOIs, very little is known about their route of elimination, even after decades of use. Phenelzine (Nardil) is thought to undergo acetylation in the liver, and there are many people who are slow acetylators-as many as 50% of whites and blacks.

However, there is very little evidence that this is clinically important, perhaps because the business end of MAOI elimination is the actual covalent bond that forms when the MAOI attaches to the MAO enzyme. The actual half-life of conventional irreversible MAOIs (e.g., Parnate, Nardil) is just a few hours. The reason their clinical effects persist for 2 weeks or more is that it takes that long for the body to generate new, un-bonded MAO enzymes--all of which has nothing to do with slow or fast metabolism in the liver.

In short, it's unlikely that a person with reduced cytochrome activity will be adversely affected by a conventional MAOI for pharmacokinetic reasons. (They may still have adverse drug reactions for other reasons; e.g., the serotonin syndrome, owing to concomitant use of an SSRI or tricyclic). Personally, I'd go with one of the agents that uses multiple metabolic pathways, and check plasma levels periodically.

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September 2002

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