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The metabolic inhibition model which predicts the intestinal absorbability and Metabolizability of drug: Theory and experiment
Biological Procedures Onlinevolume 1, pages32–39 (1998)
The intestinal absorption of analgesic peptides (leucine enkephalin and kyotorphin) and modified peptides in rat were studied. Although these peptides were not absorbed, the absorbability (absorption clearance) of these peptides were increased in the presence of peptidase inhibitors. In order to kinetically analyze these phenomena, we proposed the metabolic inhibition model, which incorporated the metabolic clearance (metabolizability) with the absorption clearance. Metabolic activity was determined with intestinal homogenates. The higher the metabolic clearance was, the lower was the absorption clearance. The relationships between the absorption clearance and the metabolic clearance of the experimental data as well as of the theoretical values were hyperbolic. This model predicted the maximum absorption clearances of cellobiose-coupled leucine enkephalin (0.654 µl/min/cm) and kyotorphin (0.247 µl/min/cm). Details of the experimental methods are described.
Mizuma, T., Ohta, K., Koyanagi, A., Awazu, S. 1996. Improvement of intestinal absorption of leucine enkephalin by sugar coupling and peptidase inhibitors. J. Pharm. Sci. 85, 854–857.
Mizuma, K., Koyanagi, A., Awazu, S. 1997. Intestinal transport and metabolism of analgesic dipeptide, kyotorphin: rate-limiting factor in intestinal absorption of peptide as drug. Biochim. Biophys. Acta 1335, 111–119.
Takagi, H., Shiomi, H., Ueda, H., Amano, H. 1979. A novel analgesic dipeptide from bovine brain is a possible Met-enkephalin releaser. Nature 282, 410–412.
Janicki, P. K., Lipkowski, A. W. 1983. Kyotorphin and D-kyotorphin stimulate Met-enkephalin release from rat striatum in vitro. Neurosi. Lett. 43, 73–77.
Matsubayashi, K., Kojima, C., Kawajiri, S., Ono, K., Takegoshi, T., Ueda, H., Takagi, H. 1984. Hydrolytic deactivation of kyotorphin by the rodent brain homogenates and sera. J Pharmacobio-Dyn. 7, 479–484.
Ueda, H., Ming, G., Hazato, T., Katayama, T., Takagi, H. 1985. Degradation of kyotorphin by a purified membrane-bound-aminopeptidase from monkey brain: potentiation of kyotorphin-induced analgesia by a highly effective inhibitor, bestatin. Life Sci. 36, 1865–1871.
Akasaki, K., Tsuji, H. 1991. An enkephalin-degrading aminopeptidase from rat brain catalyzed the hydrolysis of a neuropeptide, kyotorphin (L-Tyr-L-Arg). Chem. Pharm. Bull. 39, 1883–1885.
Orawski, A. T., Simmons, W. H. 1992. Dipeptidase activities in rat brain synaptosomes can be distinguished on the basis of inhibition by bestatin and amastatin: identification of a kyotorphin (Tyr-Arg)-degrading enzyme. Neurochem. Res. 17, 817–820.
Geary, L. E., Wiley, K. S., Scott, W. L., Cohen, M. L. 1982. Degradation of exogenous enkephalin in the guinea-pig ileum: relative importance of aminopeptidase, enkephalinase and angiotensin converting enzyme activity. J. Pharmacol. Exp. Ther. 221, 104–111.
Cohen, M. L., Geary, L. E., Wiley, K. S. 1983. Enkephalin degradation in the guinea-pig ileum: effect of aminopeptidase inhibitors, puromycin and bestatin. J. Pharmacol. Exp. Ther. 224, 379–385.
Yamaoka, K., Tanigawara, Y., Nakagawa, T., Uno, T. 1981. A pharmacokinetic analysis program (MULTI) for microcomputer. J. Pharmacobio-Dyn. 4, 879–885.
Gibaldi, M., Perrier, D. 1982. Pharmacokinetics. Marcel Dekker, Inc. New York. 1–43.
Mizuma, T., Sakai, N., Awazu, S. 1994. Na+-Dependent transport of aminopeptidase-resistant sugar-coupled tripeptides in rat intestine. Biochem. Biophys. Res. Commun. 203, 1412–1416.
Gray, G. R. 1974. The direct coupling of oligosaccharides to protein and derivatized gels. Arch. Biochem. Biophys. 163, 426–428.
Mizuma, T., Ohta, K., Hayashi, M., Awazu, S. 1992. Intestinal active absorption of sugar-conjugated compounds by glucose transport system: implication of improvement of poorly absorbable drugs. Biochem. Pharmacol. 43, 2037–2039.
Mizuma, T, Ohta, K. and Awazu, S., unpublished data.