Document Detail

Kinetics of hydrolysis of dextran-methylprednisolone succinate, a macromolecular prodrug of methylprednisolone, in rat blood and liver lysosomes.
MedLine Citation:
PMID:  10884579     Owner:  NLM     Status:  MEDLINE    
A macromolecular prodrug of methylprednisolone (MP) was synthesized by conjugating MP with dextran with a M(W) of 70000 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 succinate (MPS) which is further hydrolyzed to MP. To investigate the suitability of DMP conjugate as a prodrug of MP for systemic administration, the kinetics of hydrolysis of the conjugate was studied in vitro in rat blood and liver lysosomes. In blood, the hydrolysis of MPS to MP was approximately ten-fold faster than that in buffer. However, the hydrolysis rate constants of DMP conjugate to MP or MPS in blood were not different from those in buffer. Overall, the hydrolysis of DMP in the rat blood occurred with a half life of approximately 25 h. Hydrolysis of MPS to MP also occurred in the liver lysosomal 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 lysosomal fraction were not 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 completely, via chemical hydrolysis. However, the conversion of MPS to MP is apparently enzymatic. The data may have significant implications for systemic administration of the prodrug.
R Mehvar; R O Dann; D A Hoganson
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of controlled release : official journal of the Controlled Release Society     Volume:  68     ISSN:  0168-3659     ISO Abbreviation:  J Control Release     Publication Date:  2000 Jul 
Date Detail:
Created Date:  2000-09-05     Completed Date:  2000-09-05     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8607908     Medline TA:  J Control Release     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  53-61     Citation Subset:  IM    
School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter, Amarillo, TX 79106, USA.
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MeSH Terms
Dextrans / blood,  pharmacokinetics*
Liver / metabolism*
Lysosomes / metabolism*
Macromolecular Substances
Methylprednisolone Hemisuccinate / blood,  pharmacokinetics*
Prodrugs / pharmacokinetics*
Rats, Sprague-Dawley
Grant Support
Reg. No./Substance:
0/Macromolecular Substances; 0/Prodrugs; 2921-57-5/Methylprednisolone Hemisuccinate; 9004-54-0/Dextrans

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