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.
| Original language | English |
|---|---|
| Pages (from-to) | 215-222 |
| Number of pages | 8 |
| Journal | Journal of Surgical Research |
| Volume | 103 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Jan 1 2002 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Surgery
Cite this
Roles of the jejunum and ileum in the first-pass effect as absorptive barriers for orally administered tacrolimus. / Shimomura, Masahiro; Masuda, Satohiro; Saito, Hideyuki; Sakamoto, Seisuke; Uemoto, Shinji; Tanaka, Koichi; Inui, Ken Ichi.
In: Journal of Surgical Research, Vol. 103, No. 2, 01.01.2002, p. 215-222.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Roles of the jejunum and ileum in the first-pass effect as absorptive barriers for orally administered tacrolimus
AU - Shimomura, Masahiro
AU - Masuda, Satohiro
AU - Saito, Hideyuki
AU - Sakamoto, Seisuke
AU - Uemoto, Shinji
AU - Tanaka, Koichi
AU - Inui, Ken Ichi
PY - 2002/1/1
Y1 - 2002/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0036352082&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036352082&partnerID=8YFLogxK
U2 - 10.1006/jsre.2002.6359
DO - 10.1006/jsre.2002.6359
M3 - Article
C2 - 11922737
AN - SCOPUS:0036352082
VL - 103
SP - 215
EP - 222
JO - Journal of Surgical Research
JF - Journal of Surgical Research
SN - 0022-4804
IS - 2
ER -