Thursday, November 15, 2007

The CYP2D6 Factor

Enzymes And Drug Abuse

Different drugs effect different people differently.

Drugs are broken down into their constituent waste products by specific sets of enzymes. A subset of the human population, variously estimated at 3% to 7%, are categorized as “poor metabolizers.” For them, a drug’s recommended dosage is often far too high. The culprit is a gene variant that codes for a liver enzyme called cytochrome P450 isoenzyme 2D6, known in shorthand as CYP2D6. Poor metabolizers produce less of this crucial enzyme, which means that drugs are broken down and excreted at a much slower pace. In these people, the recommended dose results in higher drug concentrations. This obviously can make a crucial difference in how a person reacts to the drugs.

About one out of 20 people has a mutation in the 2D6 gene that causes a lack of the enzyme, according to UC-San Francisco biochemist Ira Herskowitz. “Those people are really getting a whopping dose”(New York Times, registration required). In addition, if a person with normal CYP2D6 levels is taking several drugs that are broken down by CYP2D6, then the enzyme’s ability to degrade one drug can greatly inhibit its ability to degrade the others. This increases the possibility of adverse drug interactions, particularly among the elderly, who may already be suffering from liver disease or impaired renal function.

Drugs of abuse severely complicate these enzymatic issues, since addicts and alcoholics are not known for volunteering information about their condition to medical or hospital personnel. Poor metabolizers often have little or no reaction to codeine-based medications. Screening tests for CYP2D6 variations are becoming cheaper and more widely available.

Enzyme interactions can work the other way, too. St. John’s Wort, for example, is suspected of activating another drug breakdown enzyme, CPY3A, thereby accelerating, rather than retarding, the destruction of other drugs. The herb can alter the metabolization of Phenobarbital, tamoxifen, oral contraceptives, and antiviral medications (Science, subscription required). Drugs must be combined with caution, and people need to monitor dosages, because of the tremendous degree of metabolic variation that exists.

“Start low and go slow” is still the best advice. A 2002 report from Georgetown University’s Center for Drug Development Science found that the dosage recommendations of 21 per cent of the drugs coming to market from 1980 to 1999 were later revised. Fully 80 per cent of those revisions involved a reduction in the original recommended dose. A related survey undertaken in Europe by the World Health Organization obtained similar results. “It’s long been known that for individual subjects the dosage listed on a drug label is not necessarily the right one,” said one of the authors of the Georgetown study. Typically, the recommended dosage is set early in the testing process, after analyzing results from a limited number of volunteer subjects (New York Times, registration required.) A more rigorous analysis of initial data would help get the dosage right the first time. Metabolic profiles that screen for CYP2D6 mutations will greatly assist this process.

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