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Prodrug Metabolites: Implications for Therapeutic Drug Monitoring

¹ Department of Clinical Chemistry, Georg-August University, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany

^aAuthor for correspondence. Fax 49-551-398551; e-mail moeller@med.uni-goettingen.de.

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:

• Prodrugs themselves may cross-react in immunoassays, thereby confounding pharmacokinetic data and clinical interpretation.
  
• Prodrugs may be metabolized independently of the active drug, and the resulting metabolites may cross-react in immunoassays for the active drug.
  
• From a pharmacodynamic perspective, the contributions of prodrug, active drug, and drug metabolites to the overall pharmacological activity need to be known.
  

In this issue of Clinical Chemistry, Annesley et al. (3) report on the isolation and characterization of a novel oxymethylglucuronide metabolite of fosphenytoin, a prodrug of phenytoin. This metabolite has been identified in the plasma of uremic patients . . . [Full Text of this Article]

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