Kinetics of hydrolysis of dextran-methylprednisolone succinate, a macromolecular prodrug of methylprednisolone, in rat blood and liver lysosomes

A macromolecular prodrug of methylprednisolone (MP) was synthesized by conj ugating MP with dextran with a M-w of 70 000 through a succinic acid linker . It has been shown previously that the dextran-MP conjugate (DMP) releases MP directly or indirectly through formation of methylprednisolone succinat e (MPS) which is further hydrolyzed to MP. To investigate the suitability o f DMP conjugate as a prodrug of MP for systemic administration, the kinetic s of hydrolysis of the conjugate was studied in vitro in rat blood and live r lysosomes. In blood, the hydrolysis of MPS to MP was similar to ten-fold faster than that in buffer. However, the hydrolysis rate constants of DMP c onjugate to MP or MPS in blood were not different from those in buffer. Ove rall, the hydrolysis of DMP in the rat blood occurred with a half life of s imilar to 25 h. Hydrolysis of MPS to MP also occurred in the liver lysosoma l fraction, but not in the control samples lacking lysosomes. However, the rate constants for the hydrolysis of DMP conjugate to MP and MPS in the lys osomal fraction were nor significantly different from those in the control samples. These data suggest that the slow hydrolysis of DMP conjugate to MP or MPS in both rat blood and liver lysosomes occurs mostly, if not complet ely, via chemical hydrolysis. However, the conversion of MPS to MP is appar ently enzymatic. The data may have significant implications for systemic ad ministration of the prodrug, (C) 2000 Elsevier Science B.V. All rights rese rved.