Abstract
The contribution of the intestine to the nonlinear absorption of celiprolol in the rat was studied. After intravenous administration of 14C-celiprolol to bile duct-cannulated rats, approximately 9% of the dose was found to be associated with intestinal tissue and its contents. Microhistoautoradiography of frozen intestinal sections showed a time-dependent secretion of celiprolol from the blood into the lumen of the rat intestine. Propranolol, a lipophilic β-blocker, was also found to be secreted into the intestine in vivo and transported in epithelial cells in both a temperature- and a pH-dependent manner, although to a lesser extent than celiprolol. Consistent with the observations in rats, transport of celiprolol from the basal-lateral to the apical side was found to dominate apical-to-basal transport using human Caco-2 cell monolayers. Additionally, using isolated rat small intestinal epithelial cells, celiprolol was found also to have a time- and temperature-dependent uptake, suggesting the involvement of a carrier-mediated system in its uptake. The uptake was inhibited by 2 mM celiprolol and propranolol and was also found to be pH dependent. Saturation of the carrier-mediated secretion of celiprolol in the intestine may result in enhanced absorption of celiprolol at high doses and account for its observed nonlinear absorption.
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REFERENCES
S.-M. Kuo and J. Ziemniak. The physiological disposition of individual isomers of celiprolol—a new β-blocker. In Proceedings for the Third International SCBA Symposium and Workshop, 1990, p. 323 (abstr.)
U. Sundaram, R. G. Knickelbein, and J. W. Dobbins. PH regulation in ileum: Na+-H+ and Cl−-HCO3− exchange in isolated crypt and villus cells. Am. J. Physiol. 260:G440–G449 (1991).
M. M. Weiser. Intestinal epithelial cell surface membrane glycoprotein synthesis. J. Biol. Chem. 248:2536–2541 (1973).
S. M. Grassl and P. S. Aronson. Na+/HCO3− co-transport in basolateral membrane vesicles isolated from rabbit renal cortex. J. Biol. Chem. 261:8778–8783 (1986).
G. L. Peterson. Determination of total protein. Methods Enzymol. 91:95–119 (1983).
P. Artursson. Epithelial transport of drugs in cell culture. I. A model for studying the passive diffusion of drugs over intestinal absorption (Caco-2) cells. J. Pharm. Sci. 79:476–482 (1990).
P. Artursson and J. Karlsson. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. Res. Comm. 175:880–885 (1991).
D. C. Taylor, R. Pownall, and W. Burke. The absorption of β-adrenoceptor antagonists in rat in-situ small intestine; The effect of lipophilicity. J. Pharm. Pharmacol. 37:280–283 (1985).
M. Takano, K. Inui, T. Okano, H. Saito, and R. Hori. Carrier-mediated transport systems of tetraethylammonium in rat renal brush-border and basolateral membrane vesicles. Biochim. Biophys. Acta 773:113–124 (1984).
C. Rafizadeh, F. Roch-ramel, and C. Schali. Tetraethylammonium transport in renal brush border membrane vesicles of the rabbit. J. Pharmacol. Exp. Ther. 240:308–313 (1987).
R. H. Moseley, J. Morrissette, and T. R. Johnson. Transport of N1-methylnicotinamide by organic cation-proton exchange in rat liver membrane vesicles. Am. J. Physiol. 259:G973–G982 (1990).
C. F. George and B. S. Gruchy. Elimination of drugs by active intestinal transport. J. Pharm. Pharmacol. 31:643–648 (1979).
H. Lennernas and C. G. Regardh. Dose-dependent intestinal absorption and significant intestinal excretion (exsorption) of the beta-blocker pafenolol in the rat. Pharm. Res. 10:727–731 (1993).
F. S. Caruso, H. D. Doshan, P. H. Hernandez, R. Costello, W. Applin, and E. S. Neiss. Celiprolol: Pharmacokinetics and duration of pharmacodynamic activity. Br. J. Clin. Pract. 39(Suppl. 40):12–16 (1985).
K. Turnheim and F. Lauterbach. Interaction between intestinal absorption and secretion of monoquarternary ammonium compounds in guinea pigs—a concept for the absorption kinetics of organic cations. J. Pharmacol. Exp. Ther. 212:418–424 (1980).
S. Hsing, Z. Gatmaitan, and I. M. Arias. The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa. Gastroenterology 102:879–885 (1992).
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Kuo, SM., Whitby, B.R., Artursson, P. et al. The Contribution of Intestinal Secretion to the Dose-Dependent Absorption of Celiprolol. Pharm Res 11, 648–653 (1994). https://doi.org/10.1023/A:1018959809352
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DOI: https://doi.org/10.1023/A:1018959809352