Abstract
Purpose. This investigation was performed to study the effects of Pluronic® block copolymers and Cremophor® EL on intestinal lipoprotein processing and to investigate a potential link between lipoprotein processing and P-glycoprotein.
Methods. Caco-2 cells were used to monitor changes in lipoprotein production and secretion following exposure to excipients. Effects on P-glycoprotein were monitored using cyclosporin A as a model substrate.
Results. A range of surfactants commonly used as pharmaceutical excipients in lipid-based oral drug delivery systems, including Pluronic® block copolymers L81, P85, and F68 and Cremophor® EL, inhibited intestinal lipoprotein secretion. The effects were concentration dependent and reversible. The mechanism of inhibition appears to be related to the assembly and secretion of lipoproteins rather than to initial intracellular triglyceride synthesis. A strong correlation was found between excipient-mediated inhibition of lipoprotein secretion and inhibition of P-glycoprotein efflux, implying a link between the two biochemical processes.
Conclusions. The ability of such bioactive excipients to simultaneously manipulate different cellular processes must be considered in selecting excipients for oral drug delivery systems. Such information is particularly relevant when the drug is lipophilic, a candidate for P-glycoprotein efflux, and where intestinal lymphatic targeting via chylomicron stimulation is desirable.
Similar content being viewed by others
REFERENCES
C. M. O'Driscoll. Lipid-based formulations for intestinal lymphatic delivery. Eur. J. Pharm. Sci. 15:405–415 (2002).
D. M. Woodcock, M. E. Linsenmeyer, G. Chojnowski, A. B. Kriegler, V. Nink, and L. K. Webster. Reversal of multidrug resistance by surfactants. Br. J. Cancer 66:62–68 (1992).
M. M. Nerurkar, P. S. Burton, and R. T. Borchardt. The use of surfactants to enhance the permeability of peptides through Caco-2 cells by inhibition of an apically polarized efflux system. Pharm. Res. 13:528–534 (1996).
E. V. Batrakova, H. Y. Han, V. Y. Alakhov, D. W. Miller, and A. V. Kabanov. Effects of pluronic block copolymers on drug absorption in Caco-2 cell monolayers. Pharm. Res. 15:850–855 (1998).
P. Tso, K. L. Buch, J. A. Balint, and J. B. Rodgers. Maximal lymphatic triglyceride transport rate from the rat small intestine. Am. J. Physiol. 242:G408-G415 (1982).
J. Luchoomun and M. M. Hussain. Assembly and secretion of chylomicrons by differentiated Caco-2 cells. Nascent triglycerides and preformed phospholipids are preferentially used for lipoprotein assembly. J. Biol. Chem. 274:19565–19572 (1999).
A. Seelig. A general pattern for substrate recognition by P-glycoprotein. Eur. J. Biochem. 251:252–261 (1998).
R. E. Counsell and R. C. Pohland. Lipoproteins as potential site-specific delivery systems for diagnostic and therapeutic agents. J. Med. Chem. 25:1115–1120 (1982).
F. J. Field, E. Born, H. Chen, S. Murthy, and S. N. Mathur. Esterification of plasma membrane cholesterol and triacylglycerol-rich lipoprotein secretion in Caco-2 cells: possible role of p-glycoprotein. J. Lipid Res. 36:1533–1543 (1995).
C. M. O'Driscoll. The use of the Caco-2 model to investigate biochemical and metabolic aspects of lipid absorption. B. T. Gattefossé 91:41–46 (1998).
J. Hunter, M. A. Jepson, T. Tsuruo, N. L. Simmons, and B. H. Hirst. Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells. J. Biol. Chem. 268:14991–14997 (1993).
P. Arturrson 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).
P. Saha and J. H. Kou. Effect of solubilizing excipients on permeation of poorly water-soluble compounds across Caco-2 cell monolayers. Eur. J. Pharm. Biopharm. 50:403–411 (2000).
E. Levy, M. Mehran, and E. Seidman. Caco-2 cells as a model for intestinal lipoprotein synthesis and secretion. FASEB 9:626–635 (1995).
M. Mehran, E. Levy, M. Bendayan, and E. Seidman. Lipid, apolipoprotein, and lipoprotein synthesis and secretion during cellular differentiation in Caco-2 cells. In Vitro Cell. Dev. Biol. 33:118–128 (1997).
M. M. van Greevenbroek, D. W. Erkelens, and T. W. de Bruin. Caco-2 cells secrete two independent classes of lipoproteins with distinct density: effect of the ratio of unsaturated to saturated fatty acid. Atherosclerosis 149:25–31 (2000).
S. M. Caliph, W. N. Charman, and C. J. Porter. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J. Pharm. Sci. 89:1073–1084 (2000).
M. M. van Greevenbroek, G. van Meer, D. W. Erkelens, and T. W. de Bruin. Effects of saturated, mono-, and polyunsaturated fatty acids on the secretion of apo B containing lipoproteins by Caco-2 cells. Atherosclerosis 121:139–150 (1996).
F. J. Field, E. Albright, and S. N. Mathur. Regulation of triglyceride-rich lipoprotein secretion by fatty acids in Caco-2 cells. J. Lipid Res. 29:1427–1437 (1988).
M. G. Traber, H. J. Kayden, and M. J. Rindler. Polarized secretion of newly synthesized lipoproteins by the Caco-2 human intestinal cell line. J. Lipid Res. 28:1350–1363 (1987).
S. Saarinen-Savolainen, T. Järvinen-Savolainen, K. Araki-Sasaki, H. Watanabe, and A. Urtii. Evaluation of Cytotoxicity of various ophthalmic drugs, eye drop excipients and cyclodextrins in an immortalized human corneal epithelial cell line. Pharm. Res. 15:1275–1280 (1998).
J. Folch, M. Lees, and G. H. S. Stanley. A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226:497–509 (1957).
A. Bakillah, Z. Zhou, J. Luchoomun, and M. M. Hussain. Measurement of apolipoprotein B in various cell lines: correlation between intracellular levels and rates of secretion. Lipids 32:1113–1118 (1997).
P. F. Augustijns, T. P. Bradshaw, L. S. L. Gan, R. W. Hendren, and D. R. Thakker. Evidence for a polarized efflux system in Caco-2 cells capable of modulating cyclosporine A transport. Biochem. Biophys. Res. Commun. 197:360–365 (1993).
M. L. Phillips, C. Pullinger, I. Kroes, J. Kroes, D. A. Hardman, G. Chen, L. K. Curtiss, M. M. Gutierrez, J. P. Kane, and V. N. Schumaker. A single copy of apolipoprotein B-48 is present on the human chylomicron remnant. J. Lipid Res. 38:1170–1177 (1997).
P. Tso, D. S. Drake, D. D. Black, and S. M. Sabesin. Evidence for separate pathways of chylomicron and very low density lipoprotein assembly and transport by rat small intestine. Am. J. Physiol. 247:G599-G610 (1984).
E. V. Batrakova, S. Lee, S. Li, A. Venne, V. Alakhov, and A. Kabanov. Fundamental relationships between the composition of pluronic block copolymers and their hypersensitization effect in MDR cancer cells. Pharm. Res. 16:1373–1379 (1999).
E. V. Batrakova, S. Li, V. Y. Alakhov, and A. V. Kabanov. Selective energy depletion and sensitization of multiple drug resistant cancer cells by pluronic block copolymers. Polymer Preprints 41:1639–1640 (2000).
A. V. Kabanov, E. V. Batrakova, and V. Y. Alakhov. Pluronic block copolymers for overcoming drug resistance in cancer. Adv. Drug Deliv. Rev. 54:759–779 (2002).
K. E. Berge, H. Tian, G. A. Graf, L. Yu, N. V. Grishin, J. Schultz, P. Kwiterovitch, B. Shan, R. Barnes, and H. H. Hobbs. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290:1771–1775 (2000).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Seeballuck, F., Ashford, M.B. & O'Driscoll, C.M. The Effects of Pluronic® Block Copolymers and Cremophor® EL on Intestinal Lipoprotein Processing and the Potential Link with P-Glycoprotein in Caco-2 Cells. Pharm Res 20, 1085–1092 (2003). https://doi.org/10.1023/A:1024422625596
Issue Date:
DOI: https://doi.org/10.1023/A:1024422625596