Oxidative activation of acylguanidine prodrugs: intestinal presystemic activation in rats limits absorption and can be inhibited by co-administration of ketoconazole

Xenobiotica. 2003 Jan;33(1):93-106. doi: 10.1080/0049825021000012592.


1. The disposition of acyl prodrugs was studied to improve the delivery of a guanidine-containing parent compound with poor membrane permeability and poor absorption. 2. The prodrugs were evaluated in vitro and in vivo for conversion to drug. Prodrugs were evaluated for hydrolytic or oxidative bioactivation in intestinal homogenate and rat liver S9 or microsomes. The disposition of the prodrugs in vivo was monitored in bile duct-cannulated rats. 3. Compounds with n-alkylacyl groups were efficiently bioactivated, but were hydrolysed before absorption. 4. Hydrolytic bioactivation could be blocked in vitro by branching in the alkyl chain. These compounds showed modest improvements in absorption, despite favourable permeability. Experiments with liver microsomes demonstrated efficient NADPH-dependent oxidative bioactivation, which was proposed to occur through a CYP-mediated side chain oxidation followed by cyclization and release of parent compound. Ketoconazole co-administration yielded approximately a twofold increase in absorption. 5. The hydrolytically stable prodrugs were successful in increasing absorption of parent drug and were efficiently bioactivated, but they did not yield increased systemic levels of drug.

MeSH terms

  • Administration, Oral
  • Animals
  • Antifungal Agents / pharmacology*
  • Bile Ducts / physiology
  • Biotransformation / drug effects
  • Caco-2 Cells
  • Cell Membrane Permeability
  • Chemical Phenomena
  • Chemistry, Physical
  • Chromatography, High Pressure Liquid
  • Guanidines / metabolism*
  • Humans
  • Hydrolysis
  • In Vitro Techniques
  • Intestinal Absorption / drug effects
  • Intestinal Absorption / physiology*
  • Intestinal Mucosa / metabolism*
  • Intestines / drug effects
  • Ketoconazole / pharmacology*
  • Lipids / chemistry
  • Liver / metabolism
  • Male
  • Mass Spectrometry
  • Oxidation-Reduction
  • Prodrugs / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Spectrophotometry, Ultraviolet
  • Subcellular Fractions / metabolism


  • Antifungal Agents
  • Guanidines
  • Lipids
  • Prodrugs
  • Ketoconazole