Effects of methylprednisolone and its liver-targeted dextran prodrug on ischemia-reperfusion injury in a rat liver transplantation model.
OBJECTIVE
To evaluate the effectiveness of a liver-targeted dextran prodrug (DMP) of methylprednisolone (MP) in cold preservation-warm reperfusion injury associated with liver transplantation.


METHODS
The effects of donor pretreatment with single 5 mg/kg doses of MP or DMP on ischemia-reperfusion damage to the liver were studied after 8 or 24 h of cold preservation in both isolated perfused rat liver (IPRL) and syngeneic orthotopic rat liver transplantation (OLT) models.


RESULTS
In IPRL studies, donor pretreatment with DMP, and to a lesser degree MP, significantly improved the uptake of hyaluronic acid (HA), a marker of endothelial cell function, following 8 h of cold preservation. However, neither pretreatment was protective after 24 h of preservation. In the OLT model using 24-h-preserved livers, the seven-day survival of untreated grafts was 50%. DMP pretreatment of donors significantly improved graft survival to 100%, whereas MP pretreatment was ineffective. Additionally, only DMP significantly increased the blood glucose concentrations and decreased the plasma concentrations of tumor necrosis factor-alpha after OLT. Other measured markers of liver injury were not affected by either pretreatment.


CONCLUSIONS
Selective delivery of methylprednisolone to the liver as a donor pretreatment strategy improves 24-h preserved graft survival in the OLT model.
Chimalakonda
Anjaneya P
AP
School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter, Amarillo, Texas 79106, USA.
Mehvar
Reza
R
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D050377:Cold Ischemia / Q000009:adverse effects*; D003911:Dextrans / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects*; D006820:Hyaluronic Acid / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008775:Methylprednisolone / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D001786:Blood Glucose; D003911:Dextrans; D011355:Prodrugs; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid; D008775:Methylprednisolone