PHARMACOKINETICS OF RADIOIODINATED HUMAN AND OVINE GROWTH-HORMONES INTRANSGENIC MICE EXPRESSING BOVINE GROWTH-HORMONE

Pharmacokinetics of radioiodinated human growth hormone (hGH) and ovin e growth hormone (oGH) were studied in normal mice and in transgenic m ice carrying the bovine growth hormone (bGH) gene fused to phosphoenol pyruvate carboxykinase promoter/regulator (PEPCK-bGH). Multiexponentia l plasma decay curves were obtained in both normal and transgenic mice after a I-125-oGH injection and pharmacokinetic parameters were estim ated by fitting blood concentration data to a three compartment model. The half-life for the rapid compartment was shorter in transgenic tha n in normal mice (t1/2gamma : 1.2 +/- 0.3 vs. 2.2 +/- 0.5 min). The sl ow compartment had a t1/2alpha of 160 +/- 23 min for transgenic and 70 +/- 8 min for normal mice while the middle compartment had a t1/2beta of approximately 10 min for both groups of mice. The mean residence t imes were 167 +/- 24 and 55 +/- 5 min for transgenic and normal mice, respectively. Specific liver uptake of radioactivity after injection o f I-125-hGH or I-125-hGH was found in both groups of animals. Specific ity studies indicated that, similarly to normal mice, livers of transg enic mice possess a mixed population of somatotropic and lactogenic re ceptors. Uptake of labelled hGH by the liver was dose-dependent and th e doses that prevented 50% of liver uptake (ED50%) were 8 and 165 mug per 50 g body weight for normal and transgenic mice, respectively. The se in vivo results confirm and extend previous in vitro findings that a life-long excess of bGH increases hepatic somatotropic and lactogeni c receptors. Since elevation in growth hormone (GH) receptors was repo rted to be associated with an increase in GH binding protein (GHBP), w e suspect that both the increase in the mean residence time and the re duction in specific uptake of GH in the livers of transgenic mice may be the result of an increase in GHBP levels.