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Nasal Membrane and Intracellular Protein and Enzyme Release by Bile Salts and Bile Salt-Fatty Acid Mixed Micelles: Correlation with Facilitated Drug Transport

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Abstract

The effects of four bile salts, one fusidate derivative, and one mixed micellar formulation of bile salt-fatty acid combination on the nasal mucosal protein and enzyme release have been investigated in rats using an in situ nasal perfusion technique. Deoxycholate (NaDC) was found to possess the maximum protein solubilizing activity, followed by taurodihydrofusidate (STDHF), cholate, glycocholate (NaGC), and taurocholate (NaTC) in a descending order. The difference in protein solubilization of NaDC and NaGC was further characterized by the release of 5′-nucleotidase (5′-ND), a membrane-bound enzyme, and lactate dehydrogenase (LDH), an intra-cellular enzyme, in the perfusate. While both NaDC and NaGC caused comparable 5′-ND release from nasal membrane, intracellular LDH release was significantly higher with NaDC. The greater protein and LDH solubilizing effects of NaDC corresponded well with its faster rate of disappearance from the nasal perfusate. Therefore, the dihydroxy bile salt NaDC tends to cause intracellular damage and cell lysis, whereas the trihydroxy bile salt NaGC appears to produce primarily mucosal membrane perturbations. Linoleic acid in the form of soluble mixed micelles with glycocholate caused a further increase in nasal protein release. However, the rate and extent of nasal membrane protein release by the mixed micelles composed of 15 mM glycocholate and 5 mM linoleic acid were significantly lower than those caused by either deoxyholate or STDHF at the same concentrations. Nasal absorption of acyclovir, a non-absorbable hydrophilic model antiviral agent, was found to be enhanced in the presence of conjugated trihydroxy bile salts and bile salt-fatty acid mixed micelles. A nonlinear correlation exists between first-order nasal absorption rate constant and nasal protein release rate.

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REFERENCES

  1. G. S. M. J. E. Duchateau, J. Zuidema, W. M. Albers, and F. W. H. M. Merkus. Nasal absorption of alprenolol and metoprolol. Int. J. Pharm. 34:131–136 (1986).

    Google Scholar 

  2. C. H. Huang, R. Kimura, R. Bawarshi, and A. Hussain. Mechanism of nasal absorption of drugs. I. Physicochemical parameters influencing the rate of in situ nasal absorption of drugs in rats. J. Pharm. Sci. 74:608–611 (1985).

    Google Scholar 

  3. C. McMartin, L. E. F. Hutchison, R. Hyde, and G. E. Peters. Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity. J. Pharm. Sci. 76:535–540 (1987).

    Google Scholar 

  4. L. Illum, N. F. Farraj, S. S. Davis, B. R. Johnson, and D. T. O'Hagan. Investigation of the nasal absorption of biosynthetic human growth hormone in sheep—use of bioadhesive microsphere delivery system. Int. J. Pharm. 63:207–211 (1990).

    Google Scholar 

  5. P. Tengamnuay and A. K. Mitra. Bile salt-fatty acid mixed micelles as nasal absorption promoters of peptides. II. In vivo nasal absorption of insulin in rats and effects of mixed micelles on the morphological integrity of the nasal mucosa. Pharm. Res. 7:370–375 (1990).

    Google Scholar 

  6. S. Hirai, T. Yashiki, and H. Mima. Effects of surfactants on the nasal absorption of insulin in rats. Int. J. Pharm. 9:165–172 (1981).

    Google Scholar 

  7. G. S. Gordon, A. C. Moses, R. D. Silver, J. S. Flier, and M. C. Carey. Nasal absorption of insulin: Enhancement by hydrophobic bile salts. Proc. Natl. Acad. Sci. USA 82:7419–7423 (1983).

    Google Scholar 

  8. J. P. Longenecker, A. C. Moses, J. S. Flier, R. D. Silver, M. C. Carey, and E. J. Dubovi. Effects of sodium taurodihydrofusidate on nasal absorption of insulin in sheep. J. Pharm. Sci. 76:351–355 (1987).

    Google Scholar 

  9. M. J. M. Deurloo, W. A. J. J. Hermens, S. G. Romeyn, J. C. Verhoef, and F. W. H. M. Merkus. Absorption enhancement of intranasally administered insulin by sodium taurodihydrofusidate (STDHF) in rabbits and rats. Pharm. Res. 6:853–856 (1989).

    Google Scholar 

  10. P. A. Baldwin, C. K. Klingbeil, C. J. Grimm, and J. P. Longenecker. The effect of sodium tauro-24,25-dihydrofusidate on the nasal absorption of human growth hormone in three animal models. Pharm. Res. 7:547–552 (1990).

    Google Scholar 

  11. M. Mishima, Y. Wakita, and M. Nakano. Studies on the promoting effects of medium chain fatty acid salts on the nasal absorption of insulin in rats. J. Pharmacobiodyn. 10:624–631 (1987).

    Google Scholar 

  12. F. W. H. M. Merkus, J. C. Verhoef, S. G. Romeijn, and N. G. M. Schipper. Absorption enhancing effect of cyclodextrins on intranasally administered insulin in rats. Pharm. Res. 8:588–592 (1991).

    Google Scholar 

  13. R. Coleman, G. Holdsworth, and J. B. Finean. Detergent extraction of erythrocyte ghosts: Comparison of residues after cholate and Triton X-100 treatments. Biochim. Biophys. Acta 436:38–44 (1976).

    Google Scholar 

  14. O. S. Vyvoda, R. Coleman, and G. Holdsworth. Effects of different bile salts upon the composition and morphology of a liver plasma membrane preparation: Deoxycholate is more membrane damaging than cholate and its conjugates. Biochim. Biophys. Acta 465:68–76 (1977).

    Google Scholar 

  15. D. Billington and R. Coleman. Effects of bile salts on human erythrocytes: Plasma membrane vesiculation, phospholipid solubilization and their possible relationships to bile secretion. Biochim. Biophys. Acta 509:33–47 (1978).

    Google Scholar 

  16. S. Hirai, T. Yashiki, and H. Mima. Absorption of drugs from the nasal mucosa of rat. Int. J. Pharm. 7:317–325 (1981).

    Google Scholar 

  17. O. H. Lawry, N. J. Rosebrough, A. L. Farr, and R. J. Randall. Protein measurement with Folin phenol reagent. J. Biol. Chem. 193:265–275 (1951).

    CAS  PubMed  Google Scholar 

  18. C. L. M. Arkesteijn. A kinetic method for serum 5′-nucleotidase using stabilized glutamate dehydrogenase. J. Clin. Chem. Clin. Biochem. 14:155–158 (1976).

    Google Scholar 

  19. P. G. Cabaud and F. Wroblewski. Colorimetric measurement of lactic dehydrogenase activity of body fluids. Am. J. Clin. Pathol. 30:234 (1958).

    Google Scholar 

  20. G. Land and A. Bye. Simple high-performance liquid chromatographic method for the analysis of 9-(2-hydroxyethoxymethyl)guanine (acyclovir) in human plasma and urine. J. Chromatogr. 224:51–58 (1981).

    Google Scholar 

  21. M. J. Armstrong and M. C. Carey. The hydrophobic-hydrophilic balance of bile salts. Inverse correlation between reverse-phase high performance liquid chromatographic mobilities and micellar cholesterol-solubilizing capacities. J. Lipid Res. 23:70–80 (1982).

    Google Scholar 

  22. P. Tengamnuay and A. K. Mitra. Bile salt-fatty acid mixed micelles as nasal absorption promoters of peptides. I. Effects of ionic strength, adjuvent composition and lipid structure on the nasal absorption of [D-Arg2]kyotorphin. Pharm. Res. 7:127–133 (1990).

    Google Scholar 

  23. G. S. M. J. E. Duchateau, J. Zuidema, and F. W. H. M. Merkus. Bile salts and intranasal drug absorption. Int. J. Pharm. 31:193–199 (1986).

    Google Scholar 

  24. Y. W. Chien, K. S. E. Su, and S.-F. Chang. Nasal Systemic Drug Delivery, Marcel Dekker, New York, Basel, 1989, p. 16.

    Google Scholar 

  25. S. Muranishi. Absorption enhancers. Crit. Rev. Ther. Drug Carrier Syst. 7:1–33 (1990).

    Google Scholar 

  26. M. Goodman and B. W. Barry. Action of skin enhancers: Azone, oleic acid and decylmethylsulphoxide and DSC studies. J. Pharm. Pharmacol. 38 (Suppl.):71P (1986).

    Google Scholar 

  27. P. D. Miranda, H. C. Krasny, D. A. Page, and G. B. Elion. The disposition of acyclovir in different species. J. Pharmacol. Exp. Ther. 219:309–315 (1981).

    Google Scholar 

  28. E. R. Cooper, E. W. Merritt, and R. L. Smith. Effect of fatty acid and alcohols on the penetration of acyclovir across human skin in vitro. J. Pharm. Sci. 6:688–689 (1985).

    Google Scholar 

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Shao, Z., Mitra, A.K. Nasal Membrane and Intracellular Protein and Enzyme Release by Bile Salts and Bile Salt-Fatty Acid Mixed Micelles: Correlation with Facilitated Drug Transport. Pharm Res 9, 1184–1189 (1992). https://doi.org/10.1023/A:1015808023310

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