An natural overdose of CYP2D6, and a danger to nursing infants

The cytochrome P450 family has been receiving a lot of attention lately at the FDA. This family is manufactured in the liver and is often found in the small intestines (and other places, as I’ve just found out — some drugs are metabolized by P450 enzymes in the lungs). These enzymes metabolize food and drugs, and are often the targets of investigation in drug-drug interaction. Some estimates put the number of drugs metabolized by this family at 25% of what we throw at them.

One of the enzymes, CYP2D6, metabolizes such compounds as dextromethorphan (the active ingredient in cough syrup) and codeine. Codeine, it turns out, is metabolized by CYP2D6 into morphine.

It turns out that humans have a fairly wide variance in the amount of CYP2D6 they manufacture. Approximately 1% of Caucasians, 10% of S. Europeans, and 30% of Ethiopians possess multiple copies of the genes that are responsible for CYP2D6 manufacture, so they become “ultra-metabolizers” of particular drugs, including dextromethorphan (which means that cough syrup has little effect) and codeine (which, in this case, enhances the action of codeine because it’s the _metabolite_ — morphine — that does the pain killing).

This can turn “dangerous in a nursing mother”: who take codeine to ease post-delivery pain. The excess morphine is expressed in the breastmilk, which in turn can be presented to an infant in levels much higher than lethal.

Of note is the “related story”: I blogged about earlier, where they isolated the compound in grapefruit juice that inhibits CYP2A4 (related in function to CYP2D6). It turns out that CYP2A4 metabolizes the popular statin (cholesterol-lowering) family of drugs, so that drinking grapefruit juice is contraindicated while taking statins (otherwise, you would easily overdose at prescribed levels and have lots of problems with your muscles).

[5pm update]: (Read this only if you are interested in the science; this has little to do directly with the nursing mothers article.) It turns out that “Dextromethorphan”: (active ingredient in OTC(Over-the-Counter) cough syrup) is metabolized by the CYP2D6 pathway into “Dextrorphan”:, and also by the CYP3A4 (the one inhibited by grapefruit juice) into 3-methoxymorphinan. Both of these are metabolized into 3-hydroxymorphinan. I’m not sure about the pharmacological activity of 3-methoxymorphinan and 3-hydroxymorphinan, but I do know that dextrorphan is about as active as dextromethorphan.

At any rate, if CYP2D6 is inhibited (and certainly if both are inhibited), bad things can happen at lower doses of dextromethorphan than you would otherwise expect. Antidepressants tend to hold back CYP2D6, so if you take those, watch the cough syrup. Ironically, if we follow the logic above, antidepressants should hamper the formation of morphine from codeine, but for heaven’s sake, don’t trust a biostatistician blogger posting on biochemical and medical matters for your health advice!

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