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Nasal recombinant hirudin-2 delivery: absorption and its mechanism in vivo and in vitro studies.

The objective of this study was to investigate the feasibility of systemic absorption of recombinant hirudin-2 (rHV2) by nasal delivery, and its possible absorption mechanism. The degradation of rHV2 in the nasal tissue homogenate and extracts of mucosae of rabbit, as well as the degradation inhibition of enzyme inhibitor (bacitracin) was evaluated. The bioavailability of rHV2 and the improvement with enhancers, after nasal administration in rats was investigated. For further understanding of the transport and uptake characteristics of rHV2, in vitro transport experiment under various conditions using diffusion chamber technique in excised rabbit nasal epithelium was performed. It was found that rHV2 underwent rapid degradation in rabbit nasal homogenate, but it was more stable in the extracts of nasal mucosae surface. Bacitracin was able to inhibit the degradation of rHV2 to certain extent. rHV2 was detected in the rat plasma by chromogenic substrate assay after nasal administration and some enhancers also significantly increased the nasal absorption of rHV2. The transport and uptake of rHV2 across nasal epithelium was concentration-dependent and unsaturated, and was significantly inhibited by low temperature, NaN(3), DNP and colchicines, while was less affected by alteration of transport direction. These results demonstrate that the possible absorption mechanism of rHV2 by nasal mucosa appears to be associated with the endocytosis as well as passive diffusion process.