High trough levels of oral FK506 induced by loss of small intestine

To establish a safe and effective usage of oral tacrolimus (FK506) in small bowel transplantation (SBTx) recipients, trough levels and area under the curve (AUC) values of FK506 were assessed using swine models SBTx and short bowel. Thirty-eight Landrace male piglets were divided into four groups as follows: Group 1, controls (n = 13), Group 2, a one-third small bowel mode l (n = 5); Group 3. a short bowel model (n = 10): and Group 4, a one-third small bowel allograft model (n = 10; five donors and five recipients). Pigl ets of Groups I and 3 were further divided into two sub-groups. according t o the route of drug administration: Groups 1a (n = 10) and 3a (n = 7) recei ved FK506 orally, and Groups 1b (n = 3) and 3b (n = 3) received FK506 intra venously. Oral or intravenous FK506 was started on postoperative day 3 kind continued until day 7 in each group. Oil day 7, trough levels and AUC valu es were measured. In Groups la, 2. 3a and 4. trough levels of FK506 were 2. 1 +/- 1.2 (p < 0.01 vs. Group 2. 3a or 4), 11.2 +/- 2.1, 23.3 +/- 4.8 (p < 0.05 vs. Group 2 or 4) and 14.6 +/- 3.0 ng/mL, and AUC values were 101 +/- 90 (p < 0.01 vs. Group 3a or 4), 319155. 808 +/- 200. and 531 +/- 113 ng.h/ mL. respectively. Both trough levels and AUC values were lowest in Group I a and highest in Group 3a. Between Groups ib and 3b, there was no significa nt difference in the blood levels of intravenous FK506. The shorter the fun ctioning residual small intestine was. the higher the trough level of oral FK506 was, while the presence or absence of small intestine did not affect blood levels of intravenous FK506. These results suggest that oral FK506 is metabolized in the functioning small intestine during its absorption. Ther efore. events which cause intestinal malfunction, such as graft rejection i n SBTx. inflammation and loss of small intestine, may adversely raise the t rough level of oral FK506.