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 its active metabolite to be clinically effective.
“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 (it binds opiate receptors better). “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 usually results in lower therapeutic effect. However, in the case of a prodrug, the “ultrarapid metabolizer” can experience drug toxicity and possibly death since they more rapidly produce the active metabolite.
