Abstract
Intestinal permeabilities of five dipeptidyl derivatives of L-α-methyldopa (I) were studied by an in situ intestinal perfusion method. The dipeptides displayed a significant increase in their permeabilities compared to L-α-methyldopa. The increases ranged from 4 to 20 times. These results suggest that the peptide transport system is less structurally specific than the amino acid transport systems and can be used as an absorption pathway for peptide analogues. The kinetic advantage demonstrated by the dipeptide, L-α-methyldopa-L-phenylalanine, over the amino acid analogue, L-α-methyldopa, suggests that the peptide carrier would be a possible route for improving the intestinal absorption of pharmacologically active amino acid analogues. Furthermore, the preliminary results of in vitro hydrolysis studies of selected dipeptidyl derivatives indicate that the peptide carrier system could be used as a base for a prodrug strategy.
Similar content being viewed by others
REFERENCES
W. S. Saari, W. Halczenko, D. W. Cochran, W. R. Dobrinska, W. C. Vincek, D. C. Titus, S. L. Gaul, and C. S. Sweet. J. Med. Chem. 27(6):713–717 (1984).
G. L. Amidon, A. E. Merfeld, and J. B. Dressman. J. Pharm. Pharmacol. 38:363–368 (1986).
A. E. Merfeld, A. R. Mlodozeniec, M. A. Cortese, J. B. Rhodes, J. B. Dressman, and G. L. Amidon. J. Pharm. Pharmacol. 38:815 (1986).
Ø. Stenboek, E. Muhre, H. E. Rugstad, E. Arnold, and T. Hansen. Eur. J. Clin. Pharmacol. 12:117–123 (1977).
C. R. Gardner. In R. T. Borchardt, A. J. Repta, and V. J. Stella (eds.), Directed Drug Delivery, Humana Press, N.J., 1985, p. 61.
B. G. Munck, In L. R. Johnson (ed.), Physiology of the Gastrointestinal Tract, Raven Press, New York, 1981, p. 1097.
D. M. Matthews, In L. D. Stegink and L. T. Filer (eds.), Aspartame. Physiology and Biochemistry, Mercel Dekker, New York, 1984, p. 29.
W. S. Saari, M. B. Freedman, R. D. Hartman, S. W. King, A. W. Raad, W. C. Randall, E. L. Engelhartdt, and R. Hirschmann. J. Med. Chem. 21(8):746–753 (1978).
S. Vikers, C. Duncan, S. White, G. Breault, R. Royals, P. DeSchepper, and K. Tempero. Drug Metab. Dispos. 6:640 (1978).
M. Dobrinska, W. Kukovetz, E. Beubler, H. Leidy, H. Gomez, J. Demetriades, and J. Bologese. J. Pharmacokinet. Biopharm. 10:587 (1982).
S. A. Adibi and Y. S. Kim. In L. R. Johnson (ed.), Physiology of the Gastrointestinal Tract, Raven Press, New York, 1981, p. 1073.
M. Hu, P. Sinko, A. de Meere, D. A. Johnson, and G. L. Amidon. J. Theor. Biol. 131:107–114 (1988).
P. Sinko, M. Hu, and G. L. Amidon. J. Controlled Release 6:165 (1987).
D. J. Boullin, R. F. Crampton, C. E. Heading, and D. Pelling. Clin. Sci. Mol. Med. 45:849 (1973).
M. L. G. Gardner and J. A. Plumb. Clin. Sci. 57:529–534 (1979).
A. Kaiser, W. Koch, M. Scheer, and U. Wolcke. Helv. Chim. Acta 53:1708 (1970).
N. Bodor, K. B. Sloan, and T. Higuchi. J. Med. Chem. 20:1435 (1977).
V. Ganapathy and F. H. Leibach. Am. J. Physiol. 249(12):G153–G160 (1985).
A. Tsuji, T. Terasaki, I. Tamai, and H. Hiroka. J. Pharm. Exp. Ther. 241(2):594–601 (1987).
T. Okano, K. I. Inui, M. Takano, and R. Hori. Biochem. Pharmcol. 35(11):1781–1786 (1986).
V. M. Rajendran, A. Harig, and K. Ramaswamy. Am. J. Physiol. 252(15):G682–G686 (1987).
D. M. Matthews and D. Burston. Clin. Sci. 67:541–549 (1984).
D. A. Johnson and G. L. Amidon. J. Theor. Biol. 131:93–106 (1988).
P. Sinko and G. L. Amidon. Pharm. Res. 5:645–650 (1988).
G. L. Amidon, P. Sinko, and D. Fleisher. Pharm. Res. 5:651–654 (1988).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hu, M., Subramanian, P., Mosberg, H.I. et al. Use of the Peptide Carrier System to Improve the Intestinal Absorption of L-α-Methyldopa: Carrier Kinetics, Intestinal Permeabilities, and In Vitro Hydrolysis of Dipeptidyl Derivatives of L-α-Methyldopa. Pharm Res 6, 66–70 (1989). https://doi.org/10.1023/A:1015855820488
Issue Date:
DOI: https://doi.org/10.1023/A:1015855820488