Critical factors on pulmonary absorption of peptides and proteins (diffusional barrier and metabolic barrier)

The diffusional barrier and the metabolic barrier in the pulmonary absorption of peptides and proteins were investigated from (1) correlation between bioavailability and molecular weight and (2) degradation in lung homogenates, respectively. The bioavailabilities of calcitonin, insulin, epidermal growth factor, interferon-γ (IFN-γ), erythropoietin (EPO) and interleukin 1-receptor (IL-1R), having molecular weights ranging from 3400 to 60 000 were 18, 9.1, 59.1, 36.8, 17.8 and 6.8%, respectively, following intratracheal administration in a rat model. Our data combined with reported values for other twelve peptides and proteins showed good correlations between bioavailability and molecular weight for proteins but poor correlations for peptides. The resistances of calcitonin and insulin in the lung homogenate were remarkably lower than those of INF-γ, EPO and IL-1R, which were hardly metabolized. The analytical results on the bioavailability, molecular weight and enzymatic degradation suggested that the dominant factors in the pulmonary absorption would be the metabolic barrier for peptides and the diffusional barrier for proteins.