PHARMACOLOGICAL CHARACTERIZATION OF A BIOSYNTHETIC TRISULFIDE-CONTAINING HYDROPHOBIC DERIVATIVE OF HUMAN GROWTH-HORMONE - COMPARISON WITH STANDARD 22-K GROWTH-HORMONE

Growth hormone is the classical anabolic hormone which promotes organ growth after binding to somatogenic target cell receptors, present in various target tissues. The present study elucidated the pharmacologic al characteristics in vitro and in vivo of human growth hormone and a recently identified by-product of a recombinant human growth hormone p reparation; i.e. a trisulfide-containing (cys 182-cys 189) hydrophobic , folding derivative of growth hormone, hydrophobic derivative-growth hormone. Standard growth hormone and hydrophobic derivative-growth hom one possessed similar characteristics in vitro, both as regards bindin g to the somatogenic receptor on the human IM-9 cell line, and the pro lactin receptor-mediated proliferation of rat Nb-2 cells. This indicat es that no change occurs in the binding characteristics in spite of a change in conformation of the molecule. Using an ELISA assay that dete cted standard and hydrophobic derivative-growth hormone equally well, the plasma pharmacokinetical profiles of the preparations following a single intravenous or subcutaneous dose were indistinguishable. Thus, following initial disposition of hydrophobic derivative-growth hormone and standard growth hormone into a volume, V1, of one to two times th e plasma volume. almost 90% of either compound disappeared from plasma during the alpha-phase of the plasma decay curve. Similar half-lives of 4-5 min, were found for hydrophobic derivative-growth homone and st andard growth hormone during this phase, indicating rapid removal of d rug from the circulation. Also, the AUC and C-max values for standard and hydrophobic derivative-growth hormone did not differ following int ravenous or subcutaneous administration. Examination of whole body aut oradiograms following dosing with I-125-labeled standard growth homone revealed intensive staining of the liver and renal cortex, suggesting elimination via these organs. Finally, and concording with the in vit ro and in vivo bioequivalence of hydrophobic derivative-growth hormone and standard growth hormone, anabolic action of the hydrophobic deriv ative-growth hormone in the tibia rest was shown to be fully retained. In conclusion, pharmacological profiling has been performed for stand ard growth hormone and a cys182-cys189 trisulfide-containing hydrophob ic growth hormone derivative, and no differences were detected between the two in vitro or in vivo.