Solution kinetics of a water-soluble hydrocortisone prodrug: hydrocortisone-21-lysinate.
Hydrocortisone-21-lysinate was synthesized as an amino acid prodrug of hydrocortisone to serve as a substrate for brush border aminopeptidases. This strategy was developed to demonstrate that an improvement in oral absorption could be obtained through reconversion in vivo. The aqueous stability of hydrocortisone-21-lysinate was studied over the pH range 3-8 at 25 degrees C. Reversible acyl migration of the lysine group between the 21- and 17-position hydroxyl groups was observed as well as hydrolysis. The observed half-life for direct hydrolysis of hydrocortisone-21-lysinate is 40 d at pH 3 and 30 min at pH 7. The relative instability at pH 7 is probably due to electrostatic stabilization of the negatively charged tetrahedral intermediate by the protonated amino groups.
D002851:Chromatography, High Pressure Liquid; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D012995:Solubility
C044786:hydrocortisone-21-lysinate; D006854:Hydrocortisone