EFFECT OF A CONJUGATED BILE-SALT ON THE PULMONARY ABSORPTION OF INSULIN IN RATS

Pulmonary delivery of insulin with sodium glycocholate (NaGC) as the absorption promoter has been investigated using intratracheal instillation method. The absolute bioavailability of insulin solution at a dose level of 1 U kg-1 was found to be 78.8% and 9.1% respectively in the presence and absence of 20 mM NaGC, representing a 9-fold increase. Significantly enhanced hypoglycemic effects were also observed following intratracheal administration of 1 U kg-1 insulin with NaGC. The pharmacological availability values were found to be 11.08, 18.97, 21.16, 23.37, and 23.44% in the presence of 0, 5, 10, 20 and 30 mM of NaGC, respectively. On the other hand, Tween 80, at a concentration of 20 mM, resulted in a pharmacological availability of only 16.04% while both surfactants exhibited considerable reductions in the air-water interfacial tension. Histological studies failed to reveal any observable alteration in the epithelial integrity even at 30 mM NaGC concentration. The mechanisms of bile salt-mediated pulmonary insulin absorption have therefore been postulated to be a combination of a number of factors including dissociation of insulin oligamers, dilation of pulmonary epithelial tight junctions, surface tension reduction, aminopeptidase inhibition, and ciliostatic effect.