Untitled

Abstract

The transepithelial transport of arginine vasopressin (AVP) across cultured rat alveolar epithelial cell monolayers was studied. At 0.1 nM donor [125I]AVP, the radiolabel flux measured in the apical-to-basolateral (AB) direction was about 10 times greater than that in the reverse (BA) direction. HPLC analyses of the basolateral receiver fluid collected at the end of these flux measurements showed that about 97% of the total [125I]label represented subspecies of AVP, whereas the apical receiver fluid contained largely intact AVP (approximately 85% of total [125I]label). Both donor fluids contained virtually no degradation products of AVP (> 99%). In the presence of an excess 0.1 mM unlabeled AVP in the apical donor fluid, the Papp for radiolabeled AVP in the AB direction was decreased by approximately 68%, while the fraction of intact AVP in the basolateral receiver fluid was increased six-fold as compared to that observed at 0.1 nM [125I]AVP alone. Under this condition, the flux of intact AVP was approximately the same in both directions. When the concentration of apical camostat mesylate, an aminopeptidase inhibitor, was varied from 0 to 2 mM, the radiolabeled flux in the AB direction (with 0.1 nM [125I]AVP in the donor fluid) was significantly decreased in a dose-dependent manner, yielding commensurably elevated concentrations of intact AVP in the basolateral receiver fluid. In contrast, leupeptin (0.5 mM), a serine protease inhibitor, was without effect. These data, taken together, suggest that apically-presented AVP undergoes proteolysis (most likely by peptidases localized at apical cell membranes of alveolar epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Strategies to Enhance Drug Absorption via Nasal and Pulmonary Routes

“…Therefore, a strategy to protect drugs against enzymatic degradation within the lung and nasal cavity may be necessary in some cases. Some of the protease inhibitors studied over the last decade in pulmonary/nasal drug administration as absorption enhancers are: nafamostat mesilate [61], aprotinin [62], bacitracin [63], soybean trypsin inhibitor [63], phosphoramidon [15], leupeptin [64], and bestatin [65]. In one study, aprotinin, bacitracin, and soybean trypsin were used as protease inhibitors in combination with other absorption enhancers (sodium glycocholate, linoleic acid-surfactant mixed micelles, and N -lauryl-β-d-maltopyranoside) and tested on rat lung for the absorption of insulin and Asu (1,7)) eel-calcitonin (ECT) [62,63].…”

Pulmonary Delivery of an Ultra-Fine Oxytocin Dry Powder Formulation: Potential for Treatment of Postpartum Haemorrhage in Developing Countries

“…Using rat alveolar cell monolayers, vasopressin (1084 Da), a peptide structurally similar to oxytocin (1007 Da), has been demonstrated to readily diffuse across the membrane intact. Furthermore, peptidase activity was found to be localised mainly in the apical plasma epithelium and not in the alveolar space, where peptide degradation was considered minimal [29] and clearance rates were inversely related to molecular weight [30]. The latter point is consistent with significantly higher absorption of desmopressin (1069 Da) previously reported across rat [31] and pig [32] lung when compared to BSA (66 kDa).…”

Polymeric Nanoparticles for Nasal Drug Delivery to the Brain: Relevance to Alzheimer's Disease

“…Some of these protease inhibitors studied in nasal drug delivery as absorption enhancers are leupeptin, bacitracin, and phosphoramidon. [155][156][157] However, formulation-based NPs, and the modulation of environmental pH, also relate to the regulation of protease activity. It should be noted that the interface of these enzymes with olfactory routes are not direct, and those enzymes make an impact on nasal drug delivery with an indirect approach.…”