Improvement of the Pulmonary Absorption of (Asu1,7)-Eel Calcitonin by Various Absorption Enhancers and Their Pulmonary Toxicity in Rats

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Abstract
The effects of absorption enhancers on the pulmonary absorption of (Asu1,7)-eel calcitonin (ECT) and their pulmonary toxicity were examined by means of in situ pulmonary experiments. The absorption of ECT from the lungs was estimated by its hypocalcemic effect. The pulmonary membrane toxicity of absorption enhancers was evaluated by the leakage of Evans Blue from the plasma into the lungs. In the absence of absorption enhancers, a slight hypocalcemic effect was obtained following intrapulmonary administration of ECT. However, we found significant hypocalcemic effects after the ECT administration with 10 mM n-lauryl beta-D-maltopyranoside (LM), 10 mM sodium glycocholate (NaGC), and 10 mM linoleic acid-HCO60 (hydrogenated caster oil) mixed micelle (MM). The plasma calcium levels decreased as the amount of LM coadministered with ECT increased. In contrast, 10 mM EDTA did not improve the pulmonary absorption of ECT. Overall, a correlation between the pulmonary absorption of ECT and local toxicity was observed in the presence of these additives. However, 1 mM LM, 10 mM NaGC, and 10 mM MM improve the pulmonary absorption of ECT with low pulmonary toxicity. These findings suggest that the use of these adjuvants would be a useful approach for improving the pulmonary absorption of ECT.