Organs that respond to and metabolize GH are enriched in cognate high-affinity receptors. However, whether isologous receptors mediate the de facto access of ligand to cellular degradative pathways is not known. To address this query, we assessed the distribution and whole-body elimination kinetics of (endogenous and exogenous) GH before and after administration of a novel, potent, and selective recombinant human (rh) GH receptor antagonist peptide, pegvisomant. Sixteen healthy young adults (nine men and seven women) participated in a double-blind, prospectively randomized, within-subject cross-over study. The intervention comprised a single sc injection of placebo vs. a high dose of pegvisomant (1 mg/kg sc) timed 62 and 74 h before the overnight sampling and day-time infusion sessions, respectively. The half-life, metabolic clearance rate (MCR), and distribution volume of GH were quantitated by way of: 1) deconvolution analysis of serum GH concentration time series collected every 10 min for 10 h; 2) exponential regression analysis of the decay of GH concentrations after a 6-min iv pulse of rhGH (1 and 10 μg/kg); 3) calculation of the MCR during constant iv infusion of rhGH (0.5 and 5.0 μg/kg every 2 h); and 4) exponential fitting of the elimination time-course of GH concentrations following cessation of each constant infusion. Concentrations of GH and pegvisomant were measured in separate, noncross-reactive, two-site monoclonal, immunofluorometric assays. Pegvisomant concentrations averaged 4860 ± 480 μg/liter (±SEM) across the infusion interval, thus exceeding low steady state GH concentrations by 3000-fold. Inhibitory efficacy of the GH receptor antagonist peptide was affirmed by way of a 34% reduction in the serum total IGF-I concentration, i.e., from 257 ± 37 (placebo) to 170 ± 24 (drug) μg/liter (P < 0.001); and a reciprocal 77% elevation of the (10-h) mean GH concentration, i.e., from 1.3 ± 0.23 (placebo) to 2.3 ± 0.42 (drug) μg/liter (P = 0.003). ANOVA disclosed that prior administration of pegvisomant (compared with placebo) did not alter: 1) the calculated half-life (minutes) of secreted GH, which averaged 15 ± 1.3 (placebo) and 14 ± 0.69 (drug); 2) the half-time of disappearance (minutes) of an iv pulse of rhGH, 15 ± 1.0 (placebo) and 13 ± 0.5 (drug) (for the 10 μg/kg dose); 3) the distribution volume (milliliters per kilogram) of rhGH, 59 ± 6.2 (placebo) and 58 ± 3.5 (drug); 4) the steady state GH concentration (micrograms per liter) attained during constant iv infusion of rhGH (at a rate of 5 μg/kg every 2 h), 18.2 ± 2.4 (placebo) and 18.3 ± 2.3 (drug); 5) the half-life (minutes) of elimination of GH from equilibrium, 16 ± 0.98 (placebo) and 16 ± 1.8 (drug); and 6) the steady state MCR (liters per kilogram per day) of rhGH, 3.8 ± 0.32 (placebo) and 3.5 ± 0.31 (drug). In ensemble, the present data refute the a priori postulate that vascular-accessible GH receptors determine the in vivo pseudoequilibrium kinetics of GH disappearance in the human.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Clinical Biochemistry
- Biochemistry, medical