Attenuation of acute rejection in a rat liver transplantation model by a liver-targeted dextran prodrug of methylprednisolone.
BACKGROUND
The use of methylprednisolone (MP) and other corticosteroids for the treatment of acute liver allograft rejection is associated with severe toxicities in nontarget tissues. Therefore, selective delivery of MP to the liver may improve its efficacy and alleviate its side effects. We investigated the effects of a novel liver-targeted dextran prodrug of MP (DMP) in an orthotopic rat liver transplantation (OLT) model.


METHODS
The model consisted of a high responder rejection strain combination (Dark Agouti donors and Lewis recipients). Liver recipients were intravenously administered saline or a single subtherapeutic dose of MP (5 mg/kg) as the parent drug (MP) or its prodrug (DMP). Different groups were then monitored for graft survival or euthanized 5 or 9 days posttransplantation. Plasma chemistry, including alkaline phosphatase and bilirubin, allograft histology, and survival duration were determined.


RESULTS
Untreated recipients exhibited elevated plasma levels of liver injury markers, progressive portal and venous inflammation and cellular infiltration in liver allografts, and a mean graft survival time (MST) of 10.5 days. MP treatment did not alter any of these parameters. In contrast, a single dose of DMP resulted in a decrease in plasma levels of liver injury markers, a decrease in histological grade of rejection on day 5, and a substantial increase in MST (27.5 days).


CONCLUSIONS
These results demonstrate attenuation of acute rejection following local (allograft) immunosuppression with a single subtherapeutic dose of MP delivered as a liver-targeted prodrug. Dextran prodrugs may be useful for selective delivery of immunosuppressants to the liver following liver transplantation.
School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Anjaneya P
AP
Chimalakonda
Donald L
DL
Montgomery
Jon A
JA
Weidanz
Imam H
IH
Shaik
Justin H
JH
Nguyen
John J
JJ
Lemasters
Eiji
E
Kobayashi
Reza
R
Mehvar
D000208:Acute Disease; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D049109:Cell Proliferation; D003911:Dextrans / Q000008:administration & dosage* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D007075:Immunoglobulin M / Q000097:blood; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007376:Interleukin-2 / Q000032:analysis; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016031:Liver Transplantation; D008775:Methylprednisolone / Q000008:administration & dosage* / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D003911:Dextrans; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011355:Prodrugs; D014409:Tumor Necrosis Factor-alpha; D000469:Alkaline Phosphatase; D001663:Bilirubin; D008775:Methylprednisolone