In vivo kinetics of a covalent growth hormone-binding protein complex.

The biologic function of the newly recognized binding proteins (BP) for human growth hormone (hGH) in human plasma is largely unknown; hGH circulates in part in complexed form in association with the BP. In a previous study we showed that the in vivo kinetics of hGH were altered in the presence of the BP. However, that study gave only qualitative information because the BP was present in excess and the complex was subject to dissociation in vivo. To gain more quantitative information about the in vivo behavior of complexed hGH, metabolic clearance (MCR), distribution volume (Vd), and degradation rate of a covalently crosslinked, stoichiometrically correct, chemically stable hGH-BP complex were measured. The MCR and the degradation rate of complexed hGH were tenfold lower than those of free hGH (P less than .001), and its Vd was significantly smaller than that for free hGH (P less than .001). The covalent complex was fully immunoreactive with polyclonal anti-hGH antibodies. We conclude that complexed hGH is protected from clearance and degradation by being restricted from access to degradation sites, including the proximal renal tubule and receptor-mediated delivery to intracellular proteolygic organelles. The data developed also yield preliminary information about the in vivo distribution of the BP itself. These data provide important guidelines for future studies regarding the in vivo effects of the BP. In addition, the results indicate that the principal epitope(s) of hGH remain(s) exposed on the outer surface of the complex.