Protective effects of gabexate mesilate on acute pancreatitis induced by tacrolimus (FK-506) in rats in which the pancreas was stimulated by caerulein.
We investigated the acute effects of the immunosuppressive agent, tacrolimus (FK-506), on the exocrine pancreas, in rats with or without stimulation of the pancreas, and evaluated the protective effects exerted by gabexate mesilate (FOY). While an intravenous injection of FK-506 did not change serum amylase levels during the 5-h observation period, this agent increased pancreatic amylase and protein content, and decreased the content of pancreatic DNA. Histologically, we observed intra-acinar vacuolization and individual cell necrosis. When the pancreas was stimulated by two intraperitoneal injections of caerulein (5 micrograms/kg) at 1-h intervals, however, which treatment did not induce any evident pancreatic change, FK-506 significantly increased serum amylase, pancreatic wet weight, and pancreatic amylase and protein, and decreased pancreatic DNA. Histologically, there were significant dose-related differences in the severity of intra-acinar vacuolization, interstitial edema, neutrophil infiltration, individual cell necrosis, and hemorrhage. Levels of intrapancreatic elastase were elevated and local pancreatic blood flow was reduced. Treatment with FOY improved the FK-506-induced acute pancreatitis, but did not increase the pancreatic blood flow. These findings indicate that FK-506 enhances abnormal pancreatic enzyme secretion and suggest that therapeutic doses of this agent can induce acute pancreatitis when the pancreas is stimulated. A protease inhibitor may protect the exocrine pancreas in patients who receive FK-506 after organ transplantation.
Ito
T
T
Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Kimura
T
T
Furukawa
M
M
Yamaguchi
H
H
Goto
M
M
Nakano
I
I
Nawata
H
H
D000681:Amylases / Q000378:metabolism; D000818:Animals; D002108:Ceruletide / Q000494:pharmacology*; D016670:Gabexate / Q000627:therapeutic use*; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010196:Pancreatic Elastase / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000009:adverse effects*
D016670:Gabexate; D002108:Ceruletide; D000681:Amylases; D010196:Pancreatic Elastase; D016559:Tacrolimus