Integrated pharmacokinetic assessment and strategy for orally effective prodrugs overcoming luminal degradation and biological membrane barriers

Because no kinetic principles have been proposed for designing orally effective prodrugs, the author recently reported a kinetic model for membrane transport of prodrugs (Chem-Bio Informatics Journal, 8, 25-32 (2008)), and proposed the kinetic classification and criteria for effective membrane-permeable prodrugs (KCCEMP). The present study addressed more practical conditions, where a prodrug is metabolized/degraded to a drug in the luminal tract after oral administration. Primary factors in orally effective prodrugs are luminal degradation/metabolism and absorption clearance (permeability), which includes the mechanism of membrane transport and metabolism in intestinal cells. The fraction of absorbed prodrug is expressed by the functions of these parameters. Based on the required improvement ratio of the absorption clearance, the kinetic classification and criteria of orally effective prodrugs (KCCOEP) are proposed as a decision tree with conditional equations for guiding kinetic assessment and strategy for the rational development of prodrugs. The assessment of lenampicillin, which was selected as an example of successful prodrugs, according to the procedure indicated a significant impact of luminal degradation/metabolism on the absorbed fraction, and suggests that most ester-type prodrugs on the market degrade in the luminal tract. Thus, a comprehensive study on the fraction of luminal degradation/metabolism and the absorption clearance (permeability) should be conducted to develop orally effective prodrugs, in particular, quantitative assessment of the fraction of contribution (fc,dd) of the drug formed from the prodrug in the luminal tract to the absorption following oral administration of the prodrug is emphasized.