title: Roles of the jejunum and ileum in the first-pass effect as absorptive barriers for orally administered tacrolimus.
abstract: BACKGROUND
  The immunosuppressant tacrolimus shows poor and variable bioavailability following oral administration in clinical use. Recently, the hepatic and intestinal metabolisms, or first-pass effect, of tacrolimus have been suggested to be responsible for its bioavailability. In the present study, we investigated the respective contribution of the jejunum and ileum to the first-pass effect of tacrolimus in rats.
  
  
  METHODS
  The metabolism of tacrolimus in everted sacs of the duodenum, jejunum, and ileum was examined. Tacrolimus was administered intravenously or intraintestinally to sham-operated, jejunum-resected, or ileum-resected rats. Blood samples were collected over a 240-min period, and whole-blood tacrolimus concentrations were measured by semiautomated microparticle enzyme immunoassay. The pharmacokinetic parameters of tacrolimus in each group were estimated.
  
  
  RESULTS
  The metabolic activity of tacrolimus appeared to be the highest in the everted sacs of the duodenum. The bioavailability of tacrolimus in the jejunum- or ileum-resected rats was higher than that in sham-operated controls. On the other hand, the time to peak concentration in the jejunum-resected rats was about twofold slower than those in ileum-resected and sham-operated rats.
  
  
  CONCLUSIONS
  These results suggested that the first-pass effect of tacrolimus in the small intestine shows regional differences and the extraction of tacrolimus in the small intestine consists of the amount of extraction in the jejunum and ileum. In addition, the ileum rather than the jejunum as a graft of segmental small bowel transplantation would be useful to avoid the adverse effects of tacrolimus.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shimomura
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saito
authors.forename: Seisuke
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D015153:Blotting, Western; D001835:Body Weight; D007082:Ileum / Q000033:anatomy & histology / Q000502:physiology* / Q000601:surgery; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007583:Jejunum / Q000033:anatomy & histology / Q000502:physiology* / Q000601:surgery; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus