Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지

Enhanced Permeation of Leucine Enkephalin and [D-Ala2]-leucine Enkephalinamide across Nasal, Rectal and Vaginal Mucosae of Rabbit

토끼의 비강, 직장 및 질 점막을 통한 로이신엔케팔린과 [D-알라2]-로이신엔케팔린아미드의 투과 증진

  • 전인구 (동덕여자대학교 약학대학) ;
  • 박인숙 (동덕여자대학교 약학대학) ;
  • 곽혜선 (동덕여자대학교 약학대학)
  • Published : 2002.06.01
Download PDF
⟨ Previous Next ⟩

Abstract

The effects of enzyme inhibitors and penetration enhancers on the permeation of leucine enkephalin (Leu-Enk) and its synthetic analog, [${D-ala}^2$]-leucine enkephalinamide (YAGFL) across the nasal, rectal and vaginal mucosae were evaluated. Enzyme inhibitors and penetration enhancers employed for Leu-Enk permeation study were amastatin(AM), thimerosal(TM) and ethylenediaminetetraacetic acid disodium salt(EDTA), and sodium taurodihydrofusidate (STDHF). Those for YAGFL permeation study were TM, benzalkonium chloride(BC) and EDTA, and STDHF, sodium deoxycholate(SDC), sodium glycholate(SGC), glycyrrhizic acid ammonium salt (GAA), L-$\alpha$-Iysophosphatidylcholine(LPC) and mixed micelle (MM, STDHF: linoleic acid = 15 mM : 5 mM). The addition of TM alone on the donor and receptor solutions for Leu-Enk permeation study across all the three kinds of mucosae failed to inhibit the degradation; it completely degraded in 6 hrs, and no permeation occurred. However, with addition of three kinds of inhibitors together, the fluxes across nasal, rectal and vaginal mucosae were $\20.7{pm}2.5$>/TEX>,$\0.3{pm}0.05$>/TEX> and $\1.4{pm}0.5$ $\mu$\mid$textrm{m}$/$\textrm{cm}^2$/hr, respectively. Moreover, the addition of STDHF in the presence of the above three inhibitors enhanced permeation across nasal, rectal and vaginal mucosae 1.3, 15 and 1.3 times, respectively. YhGFL also degraded in the donor and receptor solutions rapidly as time went. With mixed inhibitors of TM and EDTA, the percents of YAGFL remaining in the donor solutions facing nasal, rectal and vaginal mucosae were 69.7, 69.8 and 79.8%, respectively; the percent permeated increased to 10, 2.1 and 5.7%, respectively. The addition of STDHF in the presence of either BC/EDTA or TW/EDTA increased the permeation 2.2, 11.0 and 2.9 times, and 2.21, 14.0 and 2.7 times for nasal, rectal and vaginal mucosae, respectively. With SDC, SGC, GAA, LPC ud MM in the presence of TM/EDTA increased permeation; especially, they increased permeation across vaginal mucosae effectively, and the enhancement factors were 12.5, 7.6, 8.7, 5.7 and 5.5, respectively. The degradation extent of YAGFL was correlated with protein concentrations in the epidermal and serosal extracts. The flux of YAGFL across nasal mucosa increased dose-dependently.

Keywords

References

  1. Aungst, B. J., Blake, J. A. and Hussain, M. A. (1991). An in vitro evaluation of metabolism and poor membrane perme-ation impeding intestinal absorption of leucine enkephalin, and methods to increase absorption. J. Pharm. ExP, Ther. 259,139-145
  2. Brownstein, M. J. (1980). Peptidergic pathways in the central nervous system. Proc. R. Soc. B. 210, 133-149 https://doi.org/10.1098/rspb.1980.0124
  3. Choi, H. K., Flynn, G. L. aiid Amidon, G. L. (1990). Trans-dermal delivery of bioactive peptides: the effects of decylm-ethyl sulfoxide and pH on enkephalin transport. Pharm. Res. 7. 1099-1106 https://doi.org/10.1023/A:1015915922363
  4. Chun, I. K. and Chien, Y. W. (1995). Stabilization of methion-ine enkephalin in various rabbit mucosal extracts by enzyme inhibitors. Int. J. Pharm. 121, 217-231 https://doi.org/10.1016/0378-5173(95)00028-H
  5. Chun, I. K. and Yang, Y. J. (1992). Degradation and stabiliza-tion of [D-$ala^2$]-methionme enkephalinamide in various rab-bit mucosa extracts. J. Kor. Pharm. Sci. 22, 173-183
  6. Chun, I. K. and Chien, Y. W. (1993). Transmucosal delivery of methionine enkephalin I. kinetics of degradation in buff-ered solution and metabolism in various mucosal extracls. J. Pharm. Sci. 82, 373-378 https://doi.org/10.1002/jps.2600820408
  7. Chun, I. K, and Park, I. S. (1994). Enzymatic degradation of leucine enkephalin and [D-$ala^2$]-leucine enkephalinamide in various rabbit mucosa extracts. Yakhak Hoeji 38, 530-543
  8. Chun, I. K., Park, I. S. and Hyun, J. (1996). Inhibition of enzymatic degradation of leucine enkephalin and [D-$ala^2$]-leucine enkephalinamide in various rabbit mucosal extracts by inhibitors. J. Kor. Pharm. Sci. 26, 175-185
  9. Coy, D. H., Kastin, A. J., Schally, A. V., Morin, O., Caron, N. G., Labirie, P., Walker, J. M., Fertel, R., Bertson, G. G. and Sandman, C. A. (1976). Synthesis and opioid activities of stereoisomers and other D-amino acid analogs of methion-ine enkephalin. Life Sci. 73, 632-638
  10. Dzolijic, E. D. and Dzolijic, M. R. (1989). Moditication of morphine withdrawal in rats by alteration of the endoge-nous opioid system: effect of actinonin and GEMSA. Drus Dev. Res. 18, 255-261 https://doi.org/10.1002/ddr.430180309
  11. Ennis, R. D., Borden, L. and Lee, W. A. (1990). The effects of permeation enhancers on the surface morphology of the rat nasal mucosa: a scanning electron microscopy study. Pharm Res. 1, 468-475
  12. Faraj, J. A., Hussain, A. A., Aramaki, Y., Iseki, K., Kagoshima, M. and Dittert, L. W. (1990). Mechanism of nasal absorption of drugs. IV: plasma levels of radioactivity following intranasal adminisrtation of (3H)leucine enkepha-lin. J. Pharm. Sci. 79, 768-770 https://doi.org/10.1002/jps.2600790903
  13. Frederickson, J. C. A. and Geary L. E. (1982). Endogenous opioid peptides: review of physiological, Pharmacological and clinical aspects. Prog. Neurobid. 19, 16-69
  14. Friedman, D. I. and Amidon, G. L. (1991). Oral absorption of peptides: influence of pH and inhibitors on the intestinal hydrolysis of Ieu-enkephalin and analogues. Pharm. Res. 8, 93-96 https://doi.org/10.1023/A:1015842609565
  15. Gordon, G. S., Moses, A. C., Silver, R. D., Filler, J. S. and Carey, M. C. (1985). Nasal absorption of insulin: enhance-ment by hydrophobic bile salls. Proc. NatI. Acad. Sci. 82, 7419-7423 https://doi.org/10.1073/pnas.82.21.7419
  16. Hambrook, J. M., Morgan, B. A., Rance, M. J. and Smith, L. F. C. (1976). Mode of deactivation of the enkephalins by rat and human plasma and rat brain homogenates. Nature, 262, 782-783 https://doi.org/10.1038/262782a0
  17. Hersh, L. B. and McKelvy, J. F. (1981). An aminopeptidase from bovine brain which catalyzes the hydrolysis of enkephalin. J. Neurochem., 36, 171-178 https://doi.org/10.1111/j.1471-4159.1981.tb02392.x
  18. Hirai, S. Yashiki, T. and Mima, H. (1981). Mechanism for the enhancement of the nasal absorption of insulin by surfac-tants. Int. J. Pharm. 9, 173-184 https://doi.org/10.1016/0378-5173(81)90010-7
  19. Hughes, J., Smith, T. W., Kosterliz, H. W, Fothergill, L. T., Morgan, B. A. and Mon-ies, H. R. (1975). Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 158, 295-308
  20. Kerchner, G. A. and Geary, L. E. (1983). Studies on the trans-port of enkephalin-like oligopeptides in rat intestinal mucosa. J. Pharmacol. Exp. Ther. 226, 33-38
  21. Lee J. and Kellaway I. W. (2000). Combined effect of oleic acid and polyethylene glycol 200 on buccal permeation of [D-$ala^2$, D-leu5]enkephalin from a cubic phase of glyceryl monooleate. Int. J. Phann. 204, 137-144 https://doi.org/10.1016/S0378-5173(00)00490-7
  22. Longenecker, J. R, Moses, A. C., Flier, J. S., Silver, R. D., Carey, M. C. and Dubovi, E. J. (1989). Effects of sodium taurodihydrofusidate on nasal absorption of insulin in sheep. J. Pharm. Sci. 76, 351-355 https://doi.org/10.1002/jps.2600760502
  23. Morimoto, K., Akatsuchi, H., Mohsaka, K. and Kamada, A. (1985). Effect of non-ionic surfactants in a polyacrylic acid gel base on the rectal absorption of [Asu1,7]-ee1 calcitonin in rats. J. Pharm. PharmacoI. 37, 759-764 https://doi.org/10.1111/j.2042-7158.1985.tb04963.x