Plasma pharmacokinetics and tissue disposition of novel dextran-methylprednisolone conjugates with peptide linkers in rats.
The plasma and tissue disposition of two novel dextran prodrugs of methylprednisolone (MP) containing one (DMP-1) or five (DMP-5) amino acids as linkers were studied in rats. Single 5-mg/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 approximately 200-fold, the accumulations of the drug in the liver, spleen, and kidneys were significantly increased by conjugation. However, the extent of accumulation of DMP-1 in these tissues was substantially greater than that for DMP-5. Substantial amounts of MP were regenerated from both prodrugs in the liver and spleen, with the rate of release from DMP-5 being twice as fast as that from DMP-1. However, the AUCs of MP regenerated from DMP-1 in the liver and spleen were substantially higher than those after DMP-5. In contrast, in the kidneys, the AUC of MP regenerated from DMP-5 was higher than that after DMP-1 administration. These data suggest that DMP-1 may be more suitable than DMP-5 for targeting immunosuppression to the liver and spleen.
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
Suman
S
Penugonda
Hitesh K
HK
Agarwal
Keykavous
K
Parang
Reza
R
Mehvar
D000818:Animals; D003911:Dextrans / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008775:Methylprednisolone / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D010455:Peptides / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D003911:Dextrans; D007166:Immunosuppressive Agents; D010455:Peptides; D011355:Prodrugs; D008775:Methylprednisolone