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Dose Dependency of the Pharmacokinetics and Acute Lipolytic Actions of Growth Hormone

Medical Department M (Endocrinology and Diabetes) and Medical Research Laboratories (T.K.H., C.H.G., H.O., J.S.C., J.O.L.J.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; and Novo Nordisk A/S (M.H.R.), DK-2880 Bagsværd, Denmark

Address all correspondence and requests for reprints to: Troels Krarup Hansen, M.D., Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Norrebrogade 42-44, DK-8000 Aarhus C, Denmark. E-mail: tkh{at}dadlnet.dk.

Abstract

The sensitivity to GH is subject to substantial interindividual variations, which has been attributed to differences in age, sex, and body composition. We investigated 18 healthy nonobese men (aged 24–56 yr) on four occasions. The pharmacokinetics and acute lipolytic effects of GH were evaluated using iv bolus injections of either placebo or GH (1, 3, and 6 µg/kg^-1). Body composition was determined by computed tomography and bioimpedance measurements, and the lipolytic response was assessed through measurements of circulating lipid intermediates and adipose tissue microdialysis. The metabolic clearance rate was dose dependently reduced with increasing GH doses (57.2 ± 5.1, 45.2 ± 3.8, and 39.2 ± 2.4 ml/min^-1 per meter^-2 following injection of 1, 3, and 6 µg/kg^-1 GH, respectively, P < 0.001), and half-time was increased (14.2 ± 0.6, 16.2 ± 0.4, and 18.0 ± 0.5 min, respectively, P < 0.0001). The pharmacokinetic variables were not correlated to age or body composition at any GH dose, but GH-binding protein was the major predictor of metabolic clearance rate following the two highest GH doses as indicated by multivariate regression analysis (r² = 0.55, P < 0.001 and r² = 0.35, P = 0.012, respectively). There was a significant dose-response relationship between injected GH and the subsequent increments in lipid intermediates, but the integrated lipolytic response was not correlated to GH pharmacokinetics, age, or body composition at any GH dose. Taken together, our findings suggest that differences in GH-binding protein concentrations, which possibly reflect GHR expression, determine GH pharmacokinetics rather than age or body composition per se.

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