The expression of intestinal CYP3A4 in the piglet model.
OBJECTIVE
In our previous study, the blood levels of tacrolimus were higher in the short bowel and small bowel transplantation models than those in controls. Metabolism by intestinal cytochrome p450 3A4 (CYP3A4) has been reported to influence the blood level of orally administered tacrolimus. We performed immunohistochemistry to examine the localization of intestinal CYP3A4.


METHODS
Twenty-four piglets were divided into three groups: group 1 were controls (n = 11); group 2, ileal resection of 2/3 proximal small intestine (n = 5); and group 3, total small intestinal resection followed by 1/3 allotransplantation of ileum (n = 8). Tacrolimus was orally administered from postoperative days 3 to 7. On day 7, blood samplings were performed for the trough level and the calculation of area under the concentration time curve (AUC). Intestinal specimens from the jejunum, ileum, colon, and ileal graft were obtained on days 0 and 10 for immunohistochemistry of CYP3A4.


RESULTS
The trough and AUC values in group 2 were significantly higher than those in group 1. Furthermore those measurements in group 3 animals were higher than in group 2 (trough levels: 2.5 +/- 1.7, 11.2 +/- 2.1, 16.3 +/- 2.7 ng/mL and AUC values: 126 +/- 90, 319 +/- 155, 546 +/- 117 ng. h/mL). The expression levels of CYP3A4 were, jejunum > ileum > ileal graft > colon.


CONCLUSIONS
The intensity and extent of CYP3A4 staining diminished in the ileal graft showing an inverse correlation to the blood concentrations.
Nishi
K
K
Department of Pediatric Surgery, Tohoku University School of Medicine, Sendai, Japan. nishi@ped-surg.med.tohoku.ac.jp
Ishii
T
T
Wada
M
M
Amae
S
S
Sano
N
N
Nio
M
M
Hayashi
Y
Y
D000818:Animals; D003106:Colon / Q000201:enzymology / Q000637:transplantation; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007082:Ileum / Q000201:enzymology / Q000637:transplantation*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D007583:Jejunum / Q000201:enzymology / Q000637:transplantation; D013552:Swine; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000627:therapeutic use; D014184:Transplantation, Homologous / Q000502:physiology*
D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus