Prodrug metabolites: implications for therapeutic drug monitoring.

Prodrugs are analogs of active drugs that have been developed to improve the bioavailability and/or tolerability of the latter. Fosphenytoin (1 ) and mycophenolate mofetil (MMF) (2 ) are two examples of prodrugs where monitoring of the active drug, the anticonvulsant phenytoin and the immunosuppressant mycophenolic acid (MPA), respectively, is used to guide therapy. The successful application of therapeutic drug monitoring to prodrugs requires a reliable analytical methodology, which in general should be specific for the active drug and should provide timely results so that the clinician can, if necessary, institute appropriate dosage adjustments. Although HPLC-based methodology is the most specific procedure for drug measurements, immunoassays are more rapid; they may, however, be subject to interference through cross-reactivity with structurally related compounds (e.g., prodrugs and drug metabolites). This problem often is aggravated in patients with liver dysfunction or renal insufficiency because of extensive accumulation of drug metabolites. The use of prodrugs has the following implications for therapeutic drug monitoring: