Pharmacokinetics of radioiodinated human and ovine growth hormones in transgenic mice expressing bovine growth hormone

Abstract

Pharmacokinetics of radioiodinated human growth hormone (hGH) and ovine growth hormone (oGH) were studied in normal mice and in transgenic mice carrying the bovine growth hormone (bGH) gene fused to phosphoenolpyruvate carboxykinase promoter/regulator (PEPCK-bGH). Multiexponential plasma decay curves were obtained in both normal and transgenic mice after a 125I-oGH injection and pharmacokinetic parameters were estimated by fitting blood concentration data to a three compartment model. The half-life for the rapid compartment was shorter in transgenic than in normal mice (t1/2 gamma: 1.2 +/- 0.3 vs. 2.2 +/- 0.5 min). The slow compartment had a t1/2 alpha of 160 +/- 23 min for transgenic and 70 +/- 8 min for normal mice while the middle compartment had a t1/2 beta of approximately 10 min for both groups of mice. The mean residence times were 167 +/- 24 and 55 +/- 5 min for transgenic and normal mice, respectively. Specific liver uptake of radioactivity after injection of 125I-oGH or 125I-hGH was found in both groups of animals. Specificity studies indicated that, similarly to normal mice, livers of transgenic mice possess a mixed population of somatotropic and lactogenic receptors. Uptake of labelled hGH by the liver was dose-dependent and the doses that prevented 50% of liver uptake (ED50%) were 8 and 165 micrograms per 50 g body weight for normal and transgenic mice, respectively. These in vivo results confirm and extend previous in vitro findings that a life-long excess of bGH increases hepatic somatotropic and lactogenic receptors. Since elevation in growth hormone (GH) receptors was reported to be associated with an increase in GH binding protein (GHBP), we suspect that both the increase in the mean residence time and the reduction in specific uptake of GH in the livers of transgenic mice may be the result of an increase in GHBP levels.