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.

Closing the Gaps: A Full Scan of the Intestinal Expression of P-Glycoprotein, Breast Cancer Resistance Protein, and Multidrug Resistance-Associated Protein 2 in Male and Female Rats

“…Several investigations on the local distribution of ABC transporters in the human and rodent intestinal tract have been made (for example, human; Trezise et al, 1992;Fricker et al, 1996;Gotoh et al, 2000;Mottino et al, 2000;Maliepaard et al, 2001;Taipalensuu et al, 2001;Cherrington et al, 2002;rodent: Brady et al, 2002;Rost et al, 2002;Dietrich et al, 2003;Mouly and Paine, 2003;Tamura et al, 2003;Prime-Chapman et al, 2004;Valenzuela et al, 2004;Gutmann et al, 2005;Zimmermann et al, 2005;Englund et al, 2006;Johnson et al, 2006;Berggren et al, 2007). However, due to the pronounced heterogeneity of already existing studies, it is difficult to get a reliable picture of intestinal ABC transporter expression.…”

Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum

“…In the in situ single-pass perfusion model, the intestinal architecture is maintained with respect to metabolism, absorption, and exsorption (Pang et al, 1986;Zimmerman et al, 2000;Tamura et al, 2003). Various hydrolases expressed in the BBM first hydrolyze isovaleryl-PL, after which isovaleryl-PL taken up into the cell is hydrolyzed by microsomal and cytosolic esterases during absorption.…”

Novel gastroretentive sustained-release tablet of tacrolimus based on self-microemulsifying mixture: in vitro evaluation and in vivo bioavailability test

“…These include a low solubility in the intestine, extensive metabolism by CYP3A4 in the gut, and P-gp-mediated drug efflux. Regional differences in the functional expression of P-gp were investigated in the human intestine, indicating that there is higher activity of P-gp in the ileum and the colon than in the jejunum [16] . Therefore, the sustained-release gastroreten- tive tablets we prepared in this study can avoid extensive CYP3A4 metabolism and P-gp-mediated efflux by releasing tacrolimus in the upper part of the small intestine, promote the drug absorption, and further enhance the bioavailability of SME.…”

“…Similar to cyclosporin A, tacrolimus has a very narrow therapeutic window, and it exhibits large intra-and inter-individual variability of bioavailability, ranging from 4% to 89% (mean of around 25%) [16,17] . A high blood concentration will not only cause renal toxicity in the patient but also trigger the immune over-infection; however, a low concentration often leads to graft rejection.…”

“…It was reported that differences in P-gp and P450 function in each intestinal site could be a main cause of the site selectivity and large variability in tacrolimus absorption [16] . The gastroretentive drug delivery system (GRDDS) is a preferable approach to improve the oral bioavailability and variability of a drug with a narrow absorption window in the upper part of the gastrointestinal tract (ie, stomach and small intestine).…”