title: The site-specific transport and metabolism of tacrolimus in rat small intestine.
abstract: The objective of this study was to evaluate the absorption of tacrolimus by means of simultaneous perfusion of intestinal lumen and blood vessels in rats. In our previous report, the permeability of tacrolimus was found to be higher in the jejunum than in the ileum or colon, suggesting the site-dependent absorption after oral administration. However, in this article, simultaneous perfusion technique revealed that the extent of absorption into blood vessels was similar in the jejunum and the ileum regardless of the site difference in permeability as the absorption rate. In addition to the multidrug resistance-associated protein-mediated efflux, cytochrome P450 (P450)-mediated metabolism could be a possible mechanism to explain the inconsistencies in the site dependence of tacrolimus absorption. Two enzyme inhibitors, ketoconazole and midazolam, were coperfused in rat intestinal lumen with tacrolimus to specify the effect of P-gp and P450. In the jejunum, both inhibitors significantly enhanced the absorbed amount of tacrolimus, whereas the permeability was not affected. It was suggested that both inhibitors mainly suppress P450-mediated metabolism in the upper region of the intestine. In contrast, in the ileum, ketoconazole significantly enhanced both the absorbed amount and the permeability of tacrolimus. However, midazolam failed to enhance the absorption of tacrolimus, indicating the dominant role of P-glycoprotein (P-gp)-mediated efflux in the lower region. From these findings, it is concluded that the site-dependent differences in P-gp and/or P450 activity could be the prime cause of large intra- and interindividual variability in the oral absorption of tacrolimus.
authors.affiliation: Fujisawa Pharmaceutical Co., Ltd., 1-6 Kashima 2-Chome, Yodogawa-ku, Osaka, Japan 532-8514. shigeki_tamura@po.fujisawa.co.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tokunaga
authors.forename: Rinta
authors.initials: R
authors.lastname: Ibuki
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sezaki
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D051381:Rats; D016559:Tacrolimus / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016559:Tacrolimus