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Polymorphisms: Prodrugs

Most drugs are deactivated by CYP enzymes. “Poor metabolizers” experience accumulation of the parent drug to levels that could be equivalent to a drug overdose. However, some drugs are prodrugs. A prodrug is a parent drug that is inactive or significantly less active than its metabolite. The inactive or less active prodrug must be converted to it's active metabolite.
“Poor metabolizers” taking a prodrug will experience low bio-availability and, therefore, decreased therapeutic effect. An example is codeine. Codeine, in itself, is not very active and therefore is not responsible for the therapeutic effect experienced when taking the drug. Morphine, a metabolite of codeine, is much more active than the parent. “Poor metabolizers” of CYP2D6 will not metabolize codeine to morphine and will, therefore, not experience the therapeutic effect of the drug. Other examples of prodrugs are amitriptyline, which metabolizes to nortriptyline, and primidone, which metabolizes to phenobarbital.
“Ultrarapid metabolizers” will metabolize the parent drug at an accelerated rate. This results in low therapeutic effect. On the other hand, the “ultrarapid metabolizer” can experience drug toxicity and possibly death if the parent drug is a prodrug.
Our knowledge of cytochrome P450 enzymes has increased over the past few decades with advances in molecular biology. The genes coding for them have been identified, and the amino acid sequences of the individual P450 enzymes have been elucidated. Due to the polymorphic nature of CYP2D6, the genetics relating to the synthesis of this particular enzyme has been studied extensively.