Schaefer F, Baumann G, Haffner D, Faunt L M, Johnson M L, Mercado M, Ritz E, Mehls O, Veldhuis J D
Department of Pediatrics, University of Heidelberg, Germany.
J Clin Endocrinol Metab. 1996 Jan;81(1):22-31. doi: 10.1210/jcem.81.1.8550755.
To evaluate the principal determinants of the MCR and plasma t1/2 of unbound (free) GH in man, we performed steady state infusions of 3 doses of recombinant human GH during pharmacological suppression (iv octreotide) of endogenous GH secretion in 24 healthy adults and 12 patients (6 adults and 6 children) with chronic renal failure (CRF). Free plasma GH was calculated from total plasma GH (measured by immunoradiometric assay) and GH-binding protein activity (radioligand assay). The MCR of free GH was determined from free plasma GH and the rate of recombinant human GH infusion. The t1/2 of free plasma GH, and the concentration and the in vivo dissociation constant (Kd) of GH-binding protein (GHBP) were estimated by dynamic modeling of the postinfusion total plasma GH concentration decay curves. The MCR of free GH decreased and the plasma GH t1/2 increased significantly with increasing plasma GH concentrations. The MCR of free GH over its physiological concentration range was positively correlated with the body mass index as a measure of relative obesity and negatively related to age, but only at supraphysiological GH concentrations. In the adult patients with CRF, the MCR of free GH was decreased at each infusion rate by 25-38%, and the t1/2 was increased by 80-170%. Children with CRF showed a significantly lower MCR and higher t1/2 of plasma free GH than adult patients. Modeling and direct measurements of the off-rate of GH from its high affinity GHBP indicated normal dissociation rate constants but decreased molar concentrations of the GHBP in uremic plasma. We conclude that the rate of elimination of free GH from plasma in man is controlled by 1) plasma total free GH concentrations, 2) relative obesity, and 3) renal function within the physiological GH concentration range, whereas 4) age is a negative predictor of MCR only at supraphysiological GH concentrations.
为评估人体中未结合（游离）生长激素（GH）的代谢清除率（MCR）和血浆半衰期（t1/2）的主要决定因素，我们在24名健康成年人以及12名慢性肾衰竭（CRF）患者（6名成人和6名儿童）内源性GH分泌受到药物抑制（静脉注射奥曲肽）期间，对3种剂量的重组人生长激素进行了稳态输注。游离血浆GH由总血浆GH（通过免疫放射分析测定）和GH结合蛋白活性（放射性配体分析）计算得出。游离GH的MCR根据游离血浆GH和重组人生长激素输注速率确定。通过对输注后总血浆GH浓度衰减曲线进行动态建模，估算游离血浆GH的t1/2以及GH结合蛋白（GHBP）的浓度和体内解离常数（Kd）。随着血浆GH浓度升高，游离GH的MCR降低，血浆GH的t1/2显著增加。在其生理浓度范围内，游离GH的MCR与作为相对肥胖指标的体重指数呈正相关，与年龄呈负相关，但仅在超生理GH浓度时如此。在成年CRF患者中，每次输注速率下游离GH的MCR降低25% - 38%，t1/2增加80% - 170%。CRF儿童的血浆游离GH的MCR显著低于成年患者，t1/2则更高。对GH从其高亲和力GHBP上解离速率的建模和直接测量表明，解离速率常数正常，但尿毒症血浆中GHBP的摩尔浓度降低。我们得出结论，在生理GH浓度范围内，人体血浆中游离GH的清除速率受以下因素控制：1）血浆总游离GH浓度；2）相对肥胖程度；3）肾功能，而4）年龄仅在超生理GH浓度时是MCR的负向预测指标。
