Kinetic assessment of luminal degradation of orally effective prodrugs for rational drug development.

Although prodrugging (prodrug derivatization) is a powerful technique for improving the pharmacokinetic characteristics of drugs, the intestinal pharmacokinetics of prodrugs has yet to be elucidated fully. A previous article reported the kinetic requirement of prodrugs to overcome membrane barriers. In the present article, the luminal degradation of prodrugs was kinetically assessed to understand crucial factors in the intestinal absorption of prodrugs and to show a rational development procedure. A kinetic model equation involving luminal degradation clearance (CL(deg)) was derived, and CL(deg) was estimated according to the equation with in vitro and in vivo reported data of two kinds of ampicillin prodrugs (lenampicillin and pivampicillin) and one acyclovir prodrug (valacyclovir). For lenampicillin ((2,2-dimethyl-1-oxopropoxy)methyl ester derivative), CL(deg) was approximately 1.7 times as large as absorption clearance (CL(abs)), whereas for pivampicillin ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester derivative), CL(deg) was approximately one tenth of CL(abs). For valacyclovir (acyclovir prodrug), CL(deg) was negligible. These results indicate that not only membrane permeability but also luminal stability should be assessed for the rational development of orally effective prodrugs, and that luminal stabilization can improve the intestinal absorption of prodrugs. A procedure was proposed to develop orally effective prodrugs considered for luminal degradation as well as membrane permeability.