Nutritional and intestinal effects of the novel immunosuppressive agents: deoxyspergualin, rapamycin, and mycophenolate mofetil.
OBJECTIVE
Transplantation of the small intestine would be an attractive therapeutic option for treatment of short bowel syndrome if effective, nontoxic immunosuppressive agents could be developed. This study examines the effect of three newly developed immuno-suppressive agents: rapamycin, deoxyspergualin, and mycophenolate mofetil, on the nutritional status and intestinal function of normal juvenile rats.


METHODS
Rapamycin (2 mg/kg every second day), deoxyspergualin (2 mg/kg every second day) and mycophenolate mofetil (MM) (25 mg/kg every second day) were injected subcutaneously for six weeks.


RESULTS
Rapamycin and deoxyspergualin caused significant reductions in weight gain without impairing feed intake. Both drugs caused small decreases in fat absorption; treatment with DSG induced an increase in permeability to 99Tc-DTPA. However, the permeability to other markers, such as mannitol and lactulose, was decreased in the rapamycin and mycophenolate mofetil-treated animals. Intestinal function in vitro was quantified using glucose flux (absorption). In the rapamycin group, there was a significant decrease in ileal uptake of glucose, with the net flux (absorption) being zero; there was an associated loss of villous size histologically. In the deoxyspergualin-treated groups, there was a decrease in the jejunal glucose flux. In the mycophenolate mofetil-treated animals, there was a decrease in jejunal with a compensatory increase in ileal glucose absorption. There were minor variations in intestinal morphology, but these were not consistent.


CONCLUSIONS
Rapamycin and deoxyspergualin in these doses cause a significant reduction in weight gain in healthy juvenile animals, and all the drugs caused changes in the active transport characteristics of the intestine. Accordingly, the use of these drugs for intestinal transplantation should be evaluated carefully for their nutritional impact.
Yanchar
N L
NL
Department of Surgery, University of Alberta, Mackenzie Health Sciences Centre, Edmonton, Canada.
Fedorak
R N
RN
Kneteman
N M
NM
Sigalet
D L
DL
D000818:Animals; D004435:Eating / Q000187:drug effects*; D005769:Gastrointestinal Motility / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects*; D007792:Lactulose / Q000378:metabolism; D008297:Male; D008353:Mannitol / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D011090:Polyenes / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus; D015430:Weight Gain / Q000187:drug effects
D006146:Guanidines; D007166:Immunosuppressive Agents; D011090:Polyenes; D008353:Mannitol; D007792:Lactulose; D009173:Mycophenolic Acid; C037258:gusperimus; D020123:Sirolimus