By some estimates, more that 25% of prescription medications are metabolized by a particular form of cytochrome P450 (CYP for short) known as CYP2D6. Some popular medications metabolized with CYP2D6 include Aricept, Strattera, Claritin, Codeine, Elavil, Inderal, Oxycontin, Prozac, Paxil, Zoloft, Vicodin, Effexor, Tofranil.

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Cytochrome P450 takes its name from “pigment at 450 nanometers” because spectrographic analysis shows that the enzyme absorbs light very strongly at that wavelength.

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It turns out that different forms of CYP2D6 have different levels of activity. It’s also known that genetic variants called Single Nucleotide Polymorphisms (geneticists call these SNPs, pronounced “snips”) are associated with the different forms of CYP2D6.

In practice, the many SNPs of CYP2D6 (genotypes) are expressed as four major human phenotypes:

Extensive Metabolizers (EMs): this is the most common or “wild type” phenotype. Individuals with this phenotype show the expected response to a standard dose of a particular drug.

Intermediate Metabolizers (IMs): these individuals can have some of the problems of poor metabolizers, though usually not as serious.

Poor Metabolizers (PMs): these are individuals in whom CYP2D6 polymorphism has resulted in an inactive enzyme.

Ultrarapid Metabolizers (UMs): these individuals have more than two copies of the gene that codes for an active from of CYP2D6

In clinical practice, most problems are associated with the PM and UM phenotypes..

If a PM takes an active drug, it will not be broken down rapidly enough with the consequence that even at standard doses they may suffer the kinds of side effects seen in an overdose. On the other hand, if PMs take a prodrug such as codeine they may not respond at all because the codeine will not have been metabolized to morphine, it’s active form (“Doc, this stuff just doesn’t work…”)

If a UM takes an active drug, he or she may not get the therapeutic effect from standard doses because the drug is being broken down and excreted too fast. Conversely, if a UM takes a prodrug at a standard dose it may build up to toxic levels in the blood.

There are genetic tests that can identify a patient’s genotype and help tailor his or her therapy for the maximum therapeutic effect and a minimum of unpleasant side-effects. These tests have yet to be widely adopted in clinical practice. Pharmacologist Dr. Mary Relling [see my next posting “Pharmacogenetics in the New York Times”] has been quoted as saying:

“Most prescribers don’t understand genetics very well. The fruits of the Human Genome Project have only been out for about five years, and a lot of doctors and pharmacists did their training before that. I’ve heard people say that medicine won’t change until there re major lawsuits against prescribers who fail to use tests to individualize therapy.”

It’s my hope that medical education—this blog, for example–rather than malpractice litigation will help spread the word about pharemacogenetic testing.

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