| Abstrakt: |
Aminopeptidase inhibitors may be useful for improving the systemic bioavailability of peptide drugs administered nasally or by other routes. Preferably, their effects would be rapidly reversible. The recovery of peptide hydrolytic activity after exposure of the rat nasal cavity to various aminopeptidase inhibitors was evaluated. Leucine enkephalin (0.1 mM) was used as a model peptide which is predominantly metabolized by aminopeptidases nasally. All experiments involved in situ perfusion of the rat nasal cavity with leucine enkephalin and the inhibitor for 90 min, followed by a washout with saline, and finally a second experimental phase of perfusion with leucine enkephalin but no inhibitor. Boroleucine (0.1 μM) was a potent inhibitor of leucine enkephalin metabolism, and, after its removal, the leucine enkephalin metabolism rate returned to control levels. Much higher concentrations of bestatin (0.1 mM) and puromycin (1 mM) did not inhibit leucine enkephalin metabolism as much as did boroleucine. Furthermore, when these inhibitors were washed out, the rates of leucine enkephalin disappearance rebounded to higher than control levels. With bestatin this could have been partially due to membrane disruption, as evidenced by significantly increased protein concentrations in the perfusates. However, protein release was much lower than that caused by sodium glycocholate, a nasal membrane permeation enhancer. In considering the use of peptidase inhibitors as pharmaceutical adjuvants for peptide drugs, the aminoboronic acid derivatives, including boroleucine, have the advantages of efficacy at very low concentrations and reversibility of effects. |
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