Physiological Processes and Dynamics in the Disposition of Small and Large Doses of Biologically Active and Inactive 131I-Insulins in the Rat

Abstract

Abstract The physiological disposition of single intravenous injections of biologically active 131I-labeled insulin of high specific activity containing an average of 0.8 atom of total iodine per molecule of insulin (mol wt 6000) and of biologically inactive 131I-insulin containing an average of 6 atoms of iodine per molecule were compared in the rat over a 3-hour interval at two dose levels: tracer or physiological levels (50 to 100 microunits/100 g of rat body weight), and large or pharmacological levels (105 microunits/100 g of rat body weight). Trichloracetic acid (TCA)-precipitable radioactivity was considered to reflect intact insulin species, whereas TCA-soluble radioactivity was considered to reflect products of degradation. Analysis of the data was directed as much as possible at determining the role of fundamental processes such as diffusion, mechanisms of chemical reaction, and transport of species in the distribution of 131I-insulin and its reaction products in the body of the rat. The data obtained in this study have been interpreted as indicating that 131I-insulin species are exchanged between the plasma and various body compartments by unsteady state molecular diffusion processes in which the body compartments behave as semi-infinite homogeneous media. Superimposed on the diffusional processes are chemical reaction processes occurring in the liver and kidney, with both organs behaving as semibatch reactor systems with a critical volumetric capacity, which must be achieved before significant reaction occurs, of about 3.7 per cent of the injected 131I dose per g of organ. The degradation of 131I species in the liver and kidney appears to occur by a reaction which is second order with respect to the reactant species. Both TCA-soluble and TCA-precipitable species of biologically active 131I-insulin are degraded in the liver and kidney. Apparent reaction rate constants in the liver are 0.065 and 0.080 (%)-1 (min)-1 for TCA-precipitable and TCA-soluble species, respectively; for the kidney the rate constants are 0.030 and 0.014 (%)-1 (min)-1 for TCA-precipitable and TCA-soluble species, respectively. (The symbol, (%), denoted percentage of injected dose of 131I.) In contrast, biologically inactive 131I-insulin species appear not to be degraded by the liver and kidney. Present data suggest that the heavily iodinated, biologically inactive 131I-insulin diffuses into and out of the kidney and liver with little, if any, chemical reaction. The major muscle mass is indicated to behave as a capacitor which accepts 131I-insulin species from the plasma when plasma concentrations are high and rejects material to the plasma, for transport to other organs and tissues, when plasma concentrations are low. The existence of degradation reactions in the muscle mass is neither confirmed nor denied by present data. Concentrations of biologically inactive 131I species in the plasma, liver, and kidney were found to be independent of dosage level. In contrast, clearance of biologically active, TCA-precipitable 131I from the plasma was found to be dosage level dependent, this dependence apparently arising from interaction of diffusion and reaction processes. Liver and kidney concentrations of biologically active species were, however, independent of dosage level. The simultaneous transport and reaction processes are indicated to be quite complex, so that quantitative description of them requires extensive mathematical modeling and data not yet available. A preliminary model based on the results of this study is suggested.