Abstract
Purpose. To study the in vitro intestinal permeability of a number of newly synthesised factor Xa inhibitors to better understand the poor oral absorption of these compounds.
Methods. The bidirectional transport of the fXa inhibitors was studied in the Caco-2 cell model and isolated rat ileal tissue. An attempt was made to characterize efflux mechanisms with the help of commonly used substrates and inhibitors of various transport proteins. In addition, the transport of the fXa inhibitors was studied in MDCK cells transfected with the human MDR1 gene and expressing large amounts of P-glycoprotein (Pgp).
Results. The in vitro absorptive permeability was low for all but one of the fXa inhibitors. For compounds with non-substituted amidine, a charge (due to ionisation at neutral pH) may have resulted in poor membrane partitioning. Neutral compounds with substituted amidines were effluxed from the epithelial cells. The significance of the secretion process was illustrated by the results obtained for a neutral analogue showing high absorptive Caco-2 cell permeability that was not obviated by efflux. Transport inhibition studies in Caco-2 and permeability studies in the MDR1-transfected MDCK cells consistently showed that Pgp is not involved in the secretion of fXa inhibitors. Besides efflux, metabolic liability limited the permeation of the neutral lipophilic analogues with a carbamate ester.
Conclusions. Poor intestinal permeability may be an important factor in the incomplete oral absorption of the bisbenzimidazole-type fXa inhibitors. Poor permeability may be related to poor membrane partitioning for hydrophilic analogues, whereas susceptibility to efflux transports and gastro-intestinal enzymatic degradation may limit the permeability of some of the neutral less hydrophilic derivatives.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
L. A. Harker, J. M. Maraganore, and J. Hirsh. Novel antithrombotic agents. In: R. W. Colman, J. Hirsh, V. J. Marder, and E. W. Salzman (eds.), Hemostasis and thrombosis: Basic principles and clinical practice. JP Lippincott, Philadelphia, 1994, pp. 1638-1660.
F. A. Spencer and R. C. Becker. Novel inhibitors of factor X for use in cardiovascular diseases. Curr. Cardiol. Rep. 2:395-404 (2000).
B. H. Stewart, H. O. Chan, N. Jezyk, and D. Fleisher. Discrimination between drug candidates using models for evaluation of intestinal absorption. Adv. Drug Deliv. Rev. 23:27-45 (1997).
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. Commun. 175:880-885 (1991).
F. Delie and W. Rubas. A human colonic cell line sharing similarities with enterocytes as a model to examine oral absorption: advantages and limitations of the Caco-2 model. Crit. Rev. Ther. Drug Carrier Syst. 14:221-286 (1997).
H. Saitoh, H. Fujisaki, B. J. Aungst, and K. Miyazaki. Restricted intestinal absorption of some beta-lactam antibiotics by an energy-dependent efflux system in rat intestine. Pharm. Res. 14:645-649 (1997).
I. J. Hidalgo and J. Li. Carrier-mediated transport and efflux mechanisms in Caco-2 cells. Adv. Drug Deliv. Rev. 22:53-66 (1996).
C. R. Leveille-Webster and I. M. Arias. The biology of Pgps. J. Membr. Biol. 143 89-102 (1995).
I. Sugawara, S. Akiyama, R. J. Scheper, and S. Itoyama. Lung resistance protein (LRP) expression in human normal tissues in comparison with that of MDR1 and MRP. Cancer Lett. 112:23-31 (1997).
P. Borst, R. Evers, M. Kool, and J. Wijnholds. The multidrug resistance protein family. Biochim. Biophys. Acta 1461:347-357 (1999).
T. Terao, E. Hisanaga, Y. Sai, I. Tamai, and A. Tsuji. Active secretion of drugs from the small intestinal epithelium in rats by Pgp functioning as an absorption barrier. J. Pharm. Pharmacol. 48:1083-1089 (1996).
A. Sparreboom, J. Van Asperen, U. Mayer, A. H. Schinkel, J. W. Smit, D. K. Meijer, P. Borst, W. J. Nooijen, J. Beijnen, and O. Van Tellingen. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by Pgp in the intestine. Proc. Natl. Acad. Sci. USA 94:2031-2035 (1997).
J. Van Asperen, O. Van Tellingen, A. Sparreboom, A. H. Schinkel, P. Borst, W. J. Nooijen, and J. H. Beijnen. Enhanced oral bioavailability of paclitaxel in mice treated with the Pgp blocker SDZ PSC 833. Br. J. Cancer 76:1181-1183 (1997).
H. Saitoh, M. Hatakeyama, O. Eguchi, M. Oda, and M. Takada. Involvement of intestinal Pgp in the restricted absorption of the methylprednisolone from rat small intestine. J. Pharm. Sci. 87:73-75 (1998).
M. Horio, K. V. Chin, S. J. Currier, S. Goldenberg, C. Williams, I. Pastan, M. M. Gottesman, and J. S. Handler. Transepithelial transport of drugs by the multidrug transporter in cultured Madine-Darby canine kidney cell epithelia. J. Biol. Chem. 264:14880-14884 (1989).
H. Freiser and G. H. Nancollas. prepared for publication, IUPAC Compendium of Analytical Nomenclature, Definitive Rules 1987, Blackwell Scientific Publications, Oxford, pp. 87-90.
P. Artursson, K. Karlsson, G. Ocklind, and N. G. M. Schipper. Studying transport processes in absorptive epithelia In: A. J. Shaw (ed.), Epithelial cell culture, a practical approach, IRL Press, Oxford, 1996 pp. 111-133.
G. M. Grass and S. A. Sweetana. In-vitro measurement of gastrointestinal tissue permeability using a new diffusion cell. Pharm. Res. 5:372-376 (1988).
P. Artursson, A. L. Ungell, and J. E. Löfroth. Selective paracellular permeability in tow models of intestinal absorption: Cultured monolayers of human intestinal epithelial cells and rat intestinal segments. Pharm. Res. 10:1123-1129 (1993).
A. Wikman-Larhed and P. Artursson. Co-cultures of human intestinal goblet (HT29-H) and absorptive (Caco-2) cells for studies of drug and peptide absorption. Eur. J. Pharm. Sci. 3:171-183 (1995).
P. S. Burton, R. A. Conradi, A. R. Hilgers, and N. F. Ho. Evidence for a polarized efflux system for peptides in the apical membrane of Caco-2 cells. Biochem. Biophys. Res. Commun. 190:760-766 (1993).
J. Hunter, B. H. Hirst, and N. L. Simmons. Drug absorption limited by P-glycoprotein-mediated secretory drug transport in human intestinal epithelial Caco-2 cell layers. Pharm. Res. 10:743-749 (1993).
T. Tsuruo and A. Tomida. Multidrug resistance. Anti-Cancer Drugs 6:213-218 (1995).
J. K. Chun, L. Zhang, M. Piquette-Miller, E. Lau, L. Q. Tong, and K. M. Giacomini. Characterisation of guanidine transport in human renal brush border membranes. Pharm. Res. 14:936-941 (1997).
D. Grundemann, V. Gorboulev, S. Gambaryan, M. Veyhl, and H. Koepsell. Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372:549-552 (1994).
M. Horio, K. V. Chin, S. J. Currier, S. Goldenberg, C. Williams, I. Pastan, M. M. Gottesman, and J. S. Handler. Transepithelial transport of drugs by the multidrug transporter in cultured Madine-Darby canine kidney cell epithelia. J. Biol. Chem. 264:14880-114884 (1989).
P. R. Twentyman and C. H. Versantvoort. Experimental modulation of MRP (multidrug resistance-associated protein)-mediated resistance. Eur. J. Cancer 32A:1002-1009 (1996).
T. Österberg and U. Norinder. Theoretical calculation and prediction of P-glycoprotein-interacting drugs using MolSurf parametrization and PLS statistics. Eur. J. Pharm. Sci. 10:295-303 (2000).
P. Augustijns, P. Annaert, P. Heylen, G. Van den Mooter, and R. Kinget. Drug absorption studies of prodrug esters using the Caco-2 model: evaluation of ester hydrolysis and transepithelial transport. Int. J. Pharm. 166:45-53 (1998).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Schipper, N.G.M., Österberg, T., Wrange, U. et al. In Vitro Intestinal Permeability of Factor Xa Inhibitors: Influence of Chemical Structure on Passive Transport and Susceptibility to Efflux. Pharm Res 18, 1735–1741 (2001). https://doi.org/10.1023/A:1013378731183
Issue Date:
DOI: https://doi.org/10.1023/A:1013378731183