Nitric Oxide Donors Enhance Rectal Absorption of Macromolecules in Rabbits
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Purpose. The objective of this investigation is to evaluate the potential of nitric oxide (NO) donors as a new class of absorption enhancers which may act on intestinal epithelial cells through epithelial actions of the chemical mediator, NO.
Methods. Suppositories containing NO donors and insulin were administered into the rabbit rectum. After administration of the suppository, blood samples were collected from the auricular vein. The plasma insulin and glucose concentrations were determined.
Results. The NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP, 4 mg) induced a significant increase in the rate of insulin absorption from the rectum. Administration of a suppository containing SNAP without insulin affected neither the plasma insulin nor the plasma glucose concentration. Other NO donors, NOR1 and NOR4, also induced increases in the insulin absorption. The absorption enhancement effect of SNAP was inhibited by coadministration of the NO scavenger carboxy-PTIO. SNAP also enhanced FITC-dextran (MW 4,000) absorption. Little cytotoxicity of SNAP (3.0 mg/ml) as assessed in terms of the rate of lactate dehydrogenase (LDH) release from Caco-2 cells was detected for 2 h of incubation.
Conclusions. These findings suggest that NO enhanced macromolecular absorption from the rectum without mucosal cell damage, and that NO donors can act as potent absorption enhancers.
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- 1.V. H. L. Lee, A. Yamamoto, and U. B. Kompella. Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. Crit. Rev. Ther. Drug Carrier Syst. 8:90-192 (1991).Google Scholar
- 2.H. Kajii, T. Horie, M. Hayashi, and S. Awazu. Fluorescence study of the membrane-perturbing action of sodium caprylate as related to promotion of drug absorption. J. Pharm. Sci. 77:390-392 (1988).Google Scholar
- 3.M. Tomita, M. Hayashi, and S. Awazu. Absorption-enhancing mechanism of EDTA, caprate, and decanoylcarnitine in Caco-2 cells. J. Pharm. Sci. 8:608-611 (1996).Google Scholar
- 4.E. C. Swensom and W. J. Curatolo. Intestinal permeability enhancement for proteins, peptides and polar drugs: mechanisms and potential toxicity. Adv. Drug Deliv. Rev. 8:39-92 (1992).Google Scholar
- 5.K. Nakanishi, M. Masada, and T. Nadai. Effect of pharmaceutical adjuvants on the rectal permeability of drugs. III. Effect of repeated administration and recovery of the permeability. Chem. Pharm. Bull. 31:4161-4166 (1983).Google Scholar
- 6.K. Nakanishi, A. Ogata, M. Masada, and T. Nadai. Effect of nonsteroidal anti-inflammatory drugs on the permeability of the rectal mucosa. Chem. Pharm. Bull. 32:1956-1966 (1984).Google Scholar
- 7.K. Sakai, T. M. Kutsuna, T. Nishino, Y. Fujihara, and N. Yata. Contribution of calcium ion sequestration by polyoxyethylated nonionic surfactants to the enhanced colonic absorption of p-aminobenzoic acid. J. Pharm. Sci. 75:387-390 (1986).Google Scholar
- 8.A. L. Salzman, H. Wang, P. S. Wollert, T. J. Vandermeer, C. C. Compton, A. G. Denenberg, and M. P. Fink. Endotoxin-induced ileal mucosal hyperpermeability in pigs: role of tissue acidosis. Am. J. Physiol. 266:G633-G646 (1994).Google Scholar
- 9.M. E. Duffey, B. Hainau, S. Ho, and C. J. Bentzel. Regulation of epithelial tight junction permeability by cyclic AMP. Nature 294:451-453 (1981).Google Scholar
- 10.J. A. McRoberts and N. E. Riley. Regulation of T84-cell monolayer permeability by insulin-like growth factor. Am. J. Physiol. 262:C207-C213 (1992).Google Scholar
- 11.W. F. Stenson, R. A. Easom, T. E. Riehl, and J. Turk. Regulation of paracellular permeability in Caco-2 cell monolayers by protein kinase C. Am. J. Physiol. 265:G955-G962 (1993).Google Scholar
- 12.J. L. Madara and J. Stafford. Interferon-γ directly affects barrier function of cultured intestinal epithelial monolayers. J. Clin. Invest. 83:724-727 (1989).Google Scholar
- 13.A. L. Salzman, M. J. Menconi, N. Unno, R. M. Ezzell, D. M. Casey, P. K. Gonzalez, and M. P. Fink. Nitric oxide dilates tight junctions and depletes ATP in cultured Caco-2BBe intestinal epithelial monolayers. Am. J. Physiol. 268:G361-G373 (1995).Google Scholar
- 14.Y. Watanabe, Y. Matsumoto, K. Baba, and M. Matsumoto. Pharmaceutical evaluation of hollow type suppositories. IV. Improvement of bioavailability of propranolol in rabbits after rectal administration. J. Pharmacobio-Dyn. 9:526-531 (1986).Google Scholar
- 15.A. Hyvarinen and E. A. Nikkila. Specific determination of blood glucose with o-toluidine. Clin. Chem. Acta. 7:140-143 (1962).Google Scholar
- 16.G. J. Finlay, B. C. Baguley, and W. R. Wilson. A semiautomated microculture method for investigating growth inhibitory effects of cytotoxic compounds on exponentially growing carcinoma cells. Anal. Biochem. 139:272-277 (1984).Google Scholar
- 17.M. Kato, S. Nishino, M. Ohno, S. Fukuyama, Y. Kita, Y. Hirasawa, I. Nakanishi, H. Takasugi, and K. Sakane. New reagents for controlled release of nitric oxide. Structure-stability relationships. Bioorg. Med. Chem. Lett. 6:33-38 (1996).Google Scholar
- 18.Y. Kita, K. Ohkubo, Y. Hirasawa, Y. Katayama, M. Ohno, S. Nishino, M. Kato, and K. Yoshida. FR144420, a novel, slow, nitric oxide-releasing agent. Eur. J. Pharmacol. 275:125-130 (1995).Google Scholar
- 19.K. Morimoto, H. Yamaguchi, Y. Iwakura, M. Miyazaki, E. Nakatani, T. Iwamoto, Y. Ohashi, and Y. Nakai. Effects of proteolytic enzyme inhibitors on the nasal absorption of vasopressin and an analogue. Pharm. Res. 8:1175-1179 (1991).Google Scholar
- 20.A. Yamamoto, S. Umemori, and S. Muranishi. Absorption enhancement of intrapulmonary administered insulin by various absorption enhancers and protease inhibitors in rats. J. Pharm. Pharmacol. 46:14-18 (1994).Google Scholar
- 21.K. Nishimura, Y. Nozaki, A. Yoshimi, S. Nakamura, M. Kitagawa, N. Kakeya, and K. Kitao. Studies on the promoting effects of carboxylic acid derivatives on the rectal absorption of β-lactam antibiotics in rats. Chem. Pharm. Bull. 33:282-291 (1985).Google Scholar
- 22.Y. Watanebe, Y. Matsumoto, M. Seki, M. Takase, and M. Matsumoto. Absorption enhancement of polypeptide drugs by cyclodextrains. I. Enhanced rectal absorption of insulin from hollow-type suppositories containing insulin and cyclodextrins in rabbits. Chem. Pharm. Bull. 40:3042-3047 (1992).Google Scholar
- 23.P. L. Smith, D. A. Wall, C. H. Gochoco, and G. Wilson. Oral absorption of peptides and proteins. Adv. Drug Del. Rev. 8:253-290 (1992).Google Scholar
- 24.E. K. Anderberg and P. Artursson. Epithelial transport of drugs in cell culture. VIII: Effects of sodium dodecyl sulfate on cell membrane and tight junction permeability in human intestinal epithelial (Caco-2) cells. J. Pharm. Sci. 82:392-398 (1993).Google Scholar
- 25.M. Tomita, M. Hayashi, and S. Awazu. Absorption-enhancing mechanism of sodium caprate and decanoylcarnitine in Caco-2 cells. J. Pharmacol. Exp. Ther. 272:739-743 (1995).Google Scholar
- 26.T. Lindmark, T. Nikkila, and P. Artursson. Mechanisms of absorption enhancement by medium chain fatty acids in intestinal epithelial Caco-2 cell monolayers. J. Pharmacol. Exp. Ther. 275:958-964 (1995).Google Scholar
- 27.H. H. H. W. Schmidt, T. D. Warner, K. Ishii, H. Sheng, and F. Murad. Insulin secretion from pancreatic B cells caused by Larginine-derived nitrogen oxides. Science 255:721-723 (1992).Google Scholar
- 28.R. Laffranchi, V. Gogvadze, C. Richter, and G. A. Spinas. Nitric oxide (nitrogen monoxide, NO) stimulates insulin secretion by inducing calcium release from mitochondria. Biochem. Biophys. Res. Commun. 217:584-591 (1995).Google Scholar
- 29.A. Sjoholm. Nitric oxide donor SIN-1 inhibits insulin release. Am. J. Physiol. 271:C1098-C1102 (1996).Google Scholar