Kinetic assessment of luminal degradation of orally effective prodrugs for rational drug development
| Autor: | Takashi Mizuma |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Drug
Membrane permeability media_common.quotation_subject Acyclovir Administration Oral Pharmaceutical Science Pharmacology Antiviral Agents Permeability Pivampicillin Intestinal absorption Pharmacokinetics Oral administration In vivo medicine Prodrugs media_common Models Statistical Chemistry Valine Prodrug Anti-Bacterial Agents Intestinal Absorption Drug Design Valacyclovir Ampicillin Algorithms medicine.drug |
| Zdroj: | Journal of Pharmaceutical Sciences. 99:1078-1086 |
| ISSN: | 0022-3549 |
| Popis: | 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 (CLdeg) was derived, and CLdeg 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), CLdeg was approximately 1.7 times as large as absorption clearance (CLabs), whereas for pivampicillin ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester derivative), CLdeg was approximately one tenth of CLabs. For valacyclovir (acyclovir prodrug), CLdeg 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. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1078–1086, 2010 |
| Databáze: | OpenAIRE |
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