Around 5‐10% of the US population have a genetic variation in CYP2C19 that renders the enzyme less active in the metabolism of clopidogrel. For these patients clopidogrel is not activated properly in the body, and the patients do not have therapeutically effective levels of the metabolite. Because of the potential lack of effect of prosugrel, the FDA added labeling in 2010 to clopidogrel packing to indicate the possible lack of effectiveness of the drug. This so‐called black box warning raises safety awareness and concerns for both prescribing physicians and patients. Prasugrel is in the same drug class as clopidogrel and was approved in 2009. Prasugrel is nearly identical in structure to clopidogrel. The major difference is that the thiophene ring already bears an oxygen. The ring is essentially oxidized in its administered form. In the body the drug is activated by hydrolysis of the acetate ester to form the hydroxythiophene metabolite, which forms the active form of the drug.
Prasugrel, which is activated by plasma lipases instead of CYP2C19, shows fewer variations in how it is metabolized across broad populations of patients. For this reason, prasugrel is not packaged with black box warnings. Prasugrel is an example of how understanding metabolic issues of a drug allowed the clever design of a safer version of what is otherwise a nearly identical drug. OPTIONAL‐Please participate in the online discussion forum.
Drawing prodrugs Background: Prodrugs are compounds that are converted in the body to the biologically active form of the molecule. Instructions: Do the problems below by predicting the structure of the prodrug based on the structure of its active metabolite. Learning Goal: To recognize how particular functional groups can be formed in the body through metabolic reactions. Please complete the online exercise.