Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2486096 | Journal of Pharmaceutical Sciences | 2010 | 12 Pages |
Abstract
The plasma and tissue disposition of two novel dextran prodrugs of methylprednisolone (MP) containing one (DMPâ1) or five (DMPâ5) amino acids as linkers were studied in rats. Single 5âmg/kg doses (MP equivalent) of each prodrug or MP were administered intravenously, and blood and tissue samples were collected. Prodrug and drug concentrations were quantitated using HPLC, and noncompartmental pharmacokinetic parameters were estimated. Whereas conjugation of MP with dextran in both prodrugs substantially decreased the clearance of the drug by â¼200âfold, the accumulations of the drug in the liver, spleen, and kidneys were significantly increased by conjugation. However, the extent of accumulation of DMPâ1 in these tissues was substantially greater than that for DMPâ5. Substantial amounts of MP were regenerated from both prodrugs in the liver and spleen, with the rate of release from DMPâ5 being twice as fast as that from DMPâ1. However, the AUCs of MP regenerated from DMPâ1 in the liver and spleen were substantially higher than those after DMPâ5. In contrast, in the kidneys, the AUC of MP regenerated from DMPâ5 was higher than that after DMPâ1 administration. These data suggest that DMPâ1 may be more suitable than DMPâ5 for targeting immunosuppression to the liver and spleen. © 2009 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1626-1637, 2010
Keywords
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Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Suman Penugonda, Hitesh K. Agarwal, Keykavous Parang, Reza Mehvar,