Insulin Self-association: Effects on Lung Disposition Kinetics in the Airways of the Isolated Perfused Rat Lung (IPRL)

Abstract

To characterize the kinetic dependence of pulmonary absorption and metabolism of insulin and lispro on the magnitude of their hexameric association. Hexamer content by weight percent (%Hex) in various insulin-zinc and lispro-zinc solutions were determined by quantitative centrifugal ultrafiltration and zinc titration with terpyridine (QCUF-ZTT). Each of the solutions (0.1 ml) was then administered into the airways of the IPRL of normal and experimental diabetic animals. Rate constants were determined for lung absorption (k (a)) and non-absorptive loss (k (nal); comprising mucociliary clearance and metabolism). %Hex in administered solutions ranged from 3.3 to 94.4%. Data analysis showed excellent correlations between the values for k (a) or k (nal) and %Hex, irrespective of insulin type, concentration, solution pH or ionic strength. The values for k (a) decreased (0.22 --> 0.05 h(-1)) with increasing %Hex, as did values for k (nal). At %Hex in administered solutions >/=50%, values for k (nal) approached estimates for the rate constant for mucociliary clearance, implying that lung metabolism occurred primarily with monomeric insulin. There were no differences in insulin disposition kinetics between lungs taken from experimental diabetic and sham-control animals. The kinetics of pulmonary insulin disposition depended on the magnitude of molecular self-association. Dissociated forms of insulin (dimers or monomers) in the dosing solution showed higher rates than hexamers for both lung absorption and metabolism.