Pharmacokinetic strategy for designing orally effective prodrugs overcoming biological membrane barriers: proposal of kinetic classification and criteria for membrane-permeable prodrug-likeness

Chemical modification of an active drug with promoiety to a prodrug (“prodrugging”) is a way to improve the pharmacokinetic characteristics of an active drug in the body; however, no kinetic principles have been proposed to design orally effective prodrugs to overcome biological membrane barriers. Therefore, based on a previously reported kinetic model of drug absorption [Mizuma et al., J Pharm. Sci. 85, 854 (1996)], conditional equations for the kinetic strategy of prodrugging were derived. Conditional equations contain terms of uptake (influx) and efflux transport of the prodrug and drug, and the metabolism of the prodrug to drug. Thereby, kinetic classification and criteria for effective membrane-permeable prodrugs are shown as a decision tree with conditional equations. The first point in the kinetic classification and criteria is the uptake process; second, the efflux process is vetted; finally, the metabolic process is elucidated. In some cases, metabolism is not a factor in the better absorption of prodrugs than active drugs. Experiments corresponding to particular processes were proposed, and are applicable to the design of prodrugs not only for intestinal absorption, but also for biological membrane permeation.