Abstract
Purpose. Tacrolimus, an immunosuppressive agent, has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats.
Methods. Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. In addition, the metabolism of tacrolimus in the everted sacs of the small intestine was examined.
Results. The rate of absorption of tacrolimus in the intestine was rapid, and tacrolimus was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 25% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver. In addition, tacrolimus was significantly metabolized in the everted sacs of the rat intestine.
Conclusions. The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
R. Venkataramanan, A. Swaminathan, T. Prasad, A. Jain, S. Zuckerman, V. Warty, J. McMichael, J. Lever, G. Burckart, and T. Starzl. Clinical pharmacokinetics of tacrolimus. Clin. Pharmacokinet. 29:404-430 (1995).
M. Yasuhara, T. Hashida, M. Toraguchi, Y. Hashimoto, M. Kimura, K. Inui, R. Hori, Y. Inomata, K. Tanaka, and Y. Yamaoka. Pharmacokinetics and pharmacodynamics of FK 506 in pediatric patients receiving living-related donor liver transplantations. Transplant. Proc. 27:1108-1110 (1995).
H. Sasa, Y. Hashimoto, T. Shimizu, and K. Inui. Hepatic extraction of tacrolimus in rats with experimental liver diseases. Biol. Pharm. Bull. in press.
M. Sattler, F. P. Guengerich, C. Yun, U. Christians, and K. F. Sewing. Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab. Dispos. 20:753-761 (1992).
J. C. Kolars, P. L. Stetson, B. D. Rush, M. J. Ruwart, P. Schmiedlin-Ren, E. A. Duell, J. J. Voorhees, and P. B. Watkins. Cyclosporine metabolism by P450IIIA in rat enterocytes—another determinant of oral bioavailability? Transplantation 53:596-602 (1992).
L. C. Floren, I. Bekersky, L. Z. Benet, Q. Mekki, D. Dressler, J. W. Lee, J. P. Roberts, and M. F. Hebert. Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin. Pharmacol. Ther. 62:41-49 (1997).
A. Lampen, U. Christians, A. K. Gonschior, A. Bader, I. Hackbarth, W. von Engelhardt, and K. F. Sewing. Metabolism of the macrolide immunosuppressant, tacrolimus, by the pig gut mucosa in the Ussing chamber. Br. J. Pharmacol. 117:1730-1734 (1996).
T. H. Wilson and G. Wiseman. The use of sacs of everted small intestine for the study of the transference of substances from the mucosal to the serosal surface. J. Physiol. 123:116-125 (1954).
F. C. Grenier, J. Luczkiw, M. Bergmann, S. Lunetta, M. Morrison, D. Blonski, K. Shoemaker, and M. Kobayashi. A whole blood FK 506 assay for the IMx® analyzer. Transplant. Proc. 23:2748-2749 (1991).
S. L. Beal and L. B. Sheiner. NONMEM Users Guide, University of California, San Francisco, 1992
N. Holtbecker, M. F. Fromm, H. K. Kroemer, E. E. Ohnhaus, and H. Heidemann. In vivo assessment of intestinal drug metabolism: Reply. Drug Metab. Dispos. 25:1110-1111 (1997).
K. S. Lown, R. R. Mayo, A. B. Leichtman, H. Hsiao, D. K. Turgeon, P. Schmiedlin-Ren, M. B. Brown, W. Guo, S. J. Rossi, L. Z. Benet, and P. B. Watkins. Role of intestinal P-glycoprotein (mdrl) in interpatient variation in the oral bioavailability of cyclosporine. Clin. Pharmacol. Ther. 62:248-260 (1997).
D. Y. Gomez, V. J. Wacher, S. J. Tomlanovich, M. F. Hebert, and L. Z. Benet. The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin. Pharmacol. Ther. 58:15-19 (1995).
K. E. Thummel, D. O'Shea, M. F. Paine, D. D. Shen, K. L. Kunze, J. D. Perkins, and G. R. Wilkinson. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin. Pharmacol. Ther. 59:491-502 (1996).
M. F. Fromm, D. Busse, H. K. Kroemer, and M. Eichelbaum. Differential induction of prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology 24:796-801 (1996).
P. B. Watkins. The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv. Drug Delivery Rev. 27:161-170(1997).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hashimoto, Y., Sasa, H., Shimomura, M. et al. Effects of Intestinal and Hepatic Metabolism on the Bioavailability of Tacrolimus in Rats. Pharm Res 15, 1609–1613 (1998). https://doi.org/10.1023/A:1011967519752
Issue Date:
DOI: https://doi.org/10.1023/A:1011967519752