Many medications require a metabolic transformation before they can actually have a therapeutic effect. This transformation often involves what pharmacologists call a phase 1 reaction. There are three classes of phase 1 reactions: oxidation, reduction, and hydrolysis. All three reactions tend to make drugs more water soluble and thus more able to exert their effects within target cells.

A medication that requires such a metabolic transformation before it can work is called a prodrug. A wide variety of medications are prodrugs. Codeine, Tamoxifen, Enalapril, and L-DOPA are among the many medications that are administered as prodrugs and then metabolized to active, therapeutic compounds.

The prodrug concept figures prominently in the development of rational drugs—medications that are designed for a purpose as opposed to naturally occurring compounds that have intrinsic medicinal properties. For example, several cancer chemotherapeutic drugs are administered as prodrugs that are converted to active drugs within the target cancer cell. This takes advantage of the fact that the enzymes that activate the drug exist in higher concentration within the malignant cells.

In contrast, there are other medications that are active without prior metabolic transformation. Penicillin, morphine, coumadin (Warfarin), and Losartan (COZAAR) are widely used active drugs.

A large number of both pro- and active drugs undergo phase 1 reactions catalyzed by enzymes of the cytochrome P450 system. One form of cytochrome P450, the CYP2D6 form, is involved in the phase 1 metabolism of more than 25% of all prescription medications. Molecular genetics—specifically, the emerging disciplines of pharmacogenetics and pharmacogenomics—have identified a large number of variants of CYP2D6 that are genetically determined.

The clinical implication of these genetic findings is that not everyone metabolizes a particular drug the same way. Depending on one’s genetic constitution, a drug may have effects along a continuum ranging from no effect at all to serious toxicity. The good news is that with wider acceptance of genetic testing, it will be within a physician’s reach to be able to predict who is a good candidate for a particular medication and who is not.

Although the metabolic effects exist along a continuum, pharmacogeneticists separate individuals into four main classes: poor metabolizers (PM), (EM) metabolizers (the normal type), intermediate metabolizers (IM), and ultrarapid metabolizers (UM).

Depending on the form of cytochrome P450 enzymes that an individual possesses, and on whether a medication is administered as a prodrug or an active drug, there exists a wide range of consequences. Here are some examples of what happens in various situations.

• Active drug given to a poor or intermediate metabolizer. The consequence here is that the drug is not metabolized to a form that can be easily excreted. The active drug concentration can build up to toxic levels.
• Active drug given to a ultrarapid metabolizer. The consequence here is that the drug will be rapidly degraded and never achieve therapeutic levels. Such individuals may not be helped by the medication even at extremely high doses.
• Active drug given to an extensive metabolizer. This is the desired result.
• Prodrug given to a poor or intermediate metabolizer. The consequence here is that not enough of the active drug is produced. The individual will not get he desired therapeutic effect and the prodrug concentration may become high enough to produce unintended consequences.
• Prodrug given to an ultrarapid metabolizer. This is a situation that can produce dangerous toxicity. Larger than expected amounts of the active drug are produced and may achieve toxic levels.
• Prodrug given to extensive metabolizer. Again, this is the desired result.

Another situation with important clinical implications is when an individual receives two or more drugs that compete for the same CYP2D6 enzyme. Tamoxifen is a widely prescribed estrogen receptor modulator drug, given to women who have had or are at high risk of developing breast cancer. Tamoxifen is a prodrug that requires a phase 1 reaction catalyzed by a CYP2D6 enzyme. The widely prescribed SSRI antidepressants (Prozac, Celexa, Zoloft, Paxil, and others) tend to block the action of CYP2D6. Thus, a women receiving both tamoxifen and an SSRI drug may not convert enough Tamoxifen to an active drug.

This is more than speculation. Surveys suggest that more than a quarter of all women receiving tamoxifen are also taking an SSRI antidepressant. In some cases the SSRI is given to treat the hot flashes from tamoxifen induced menopause, and in others for the treatment of depression. In either case, the interaction may render the tamoxifen ineffective.

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