Determination of metabolite pharmacokinetics for orally administered prodrugs.

The theoretical evaluation of a pharmacokinetic precursor/metabolite model was accomplished utilizing an integral approach based on clearance. Particular attention was paid to prodrugs where a single active intermediate results directly from the parent drug. This model, however, can be utilized for any drug in which a single first-pass metabolic adduct results. Complete elucidation of the first-pass and metabolic systemic pharmacokinetics is possible when plasma and urine concentration data are available after only oral drug administration. The generality of the model does not require prior knowledge of whether the metabolite was formed systemically or presystemically, and only limited metabolic pathway profiling. The model was applied to the evaluation of the angiotensin-converting enzyme inhibitor prodrug pentopril.