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 pharmacological characteristics in vitro and in vivo of human growth hormone and a recently identified by-product of a recombinant human growth hormone preparation; 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 hormone possessed similar characteristics in vitro, both as regards binding to the somatogenic receptor on the human IM-9 cell line, and the prolactin receptor-mediated proliferation of rat Nb2 cells. This indicates that no change occurs in the binding characteristics in spite of a change in conformation of the molecule. Using an ELISA assay that detected 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 the 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 hormone and standard growth hormone during this phase, indicating rapid removal of drug from the circulation. Also, the AUC and Cmax values for standard and hydrophobic derivative-growth hormone did not differ following intravenous or subcutaneous administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Thomsen
M K
MK
Novo Nordisk, Research and Development, Bagsvaerd, Denmark.
Hansen
B S
BS
Nilsson
P
P
Nowak
J
J
Johansen
P B
PB
Thomsen
P D
PD
Christiansen
J
J
D000818:Animals; D001345:Autoradiography; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D013006:Growth Hormone / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006132:Growth Plate / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D007672:Kidney Cortex / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011986:Receptors, Somatotropin / Q000378:metabolism; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D013440:Sulfides
D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; D013440:Sulfides; D013006:Growth Hormone