Comparison of cyclosporin A and tacrolimus concentrations in whole blood between jejunal and ileal transplanted rats.
Most immunosuppresive drugs are absorbed from the intestine after oral administration, although there is some difference of bioavailability between ileum and jejunum. Using an orthotopic segmental small bowel transplantation (SBT) model in rats, we studied the pharmacokinetic profiles of cyclosporin A and tacrolimus concentrations after oral intake, comparing jejunal and ileal transplanted rats. Two types of segmental SBT (jejunal and ileal SBT) in a syngeneic combination were performed. After oral administration of cyclosporin A (10mgkg(-1) or tacrolimus (5 mg kg(-1)), pharmacokinetic data were obtained from the long-surviving rats transplanted with segmental SBT. To determine the effect of additional bile on cyclosporin absorption, an emulsion of cyclosporin A with fresh bile juice was re-challenged on segmental SBT rats before killing. A histological study was also performed by use of the intestinal grafts from the killed SBT rats. A higher concentration of cyclosporin A was observed in the ileum-grafted rats than in the rats which received the jejunal grafts. Oral bioavailability of cyclosporin A in ileal SBT rats tended to be increased by addition of fresh bile juice, but that in jejunal SBT rats did not change. On the other hand, there was no significant difference of tacrolimus concentration between jejunum- and ileum-transplanted rats. Histological studies showed that the superficial mucosal layer of both grafts, but especially the ileal graft, was markedly elongated compared with that of normal intestine. The present study showed that cyclosporin A was more actively absorbed from ileum than from jejunum in SBT, but tacrolimus was absorbed equally from both sites. These data suggest that cyclosporin A concentration is satisfactorily controlled in the segmental ileal graft, while there is no difference of tacrolimus absorption between ileal and jejunal graft.
Ogino
Y
Y
Department of Clinical Pharmacology, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
Kobayashi
E
E
Fujimura
A
A
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics*; D007082:Ileum / Q000378:metabolism* / Q000637:transplantation; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism* / Q000637:transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus