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基础胰岛素类似物中工程化的可预测性和延长作用:地特胰岛素的药理学

Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir.

作者信息

Kurtzhals P

机构信息

Novo Nordisk, Bagsvaerd, Denmark.

出版信息

Int J Obes Relat Metab Disord. 2004 Sep;28 Suppl 2:S23-8. doi: 10.1038/sj.ijo.0802746.

Abstract

The suboptimal nature of the absorption profiles of human insulin formulations following subcutaneous administration has prompted the development of insulin analogues better suited for therapeutic use in diabetes mellitus. A particular challenge has been to engineer long-acting agents that do not produce unduly variable responses from one injection to another. One recent approach that has met with success has been to acylate, the insulin molecule with a fatty acid, thereby enabling reversible albumin binding. The first clinically available agent of this type is insulin detemir. Pharmacological studies have established that this principle is effective in prolonging action, primarily by retarding absorption. The solubility of insulin detemir in the vial and after injection and an important buffering mechanism effected by plasma albumin binding explain a significant decrease in within-subject variability of pharmacodynamic response observed in repeat isoglycaemic clamp studies where insulin detemir was compared to other basal insulin products. Owing to the extremely high ratio of albumin-binding sites to insulin detemir molecules at therapeutic concentrations, no safety considerations have been identified pertaining to albumin binding. The insulin detemir molecule retains the molecular pharmacological properties of native human insulin, including a physiological balance between metabolic and mitogenic potencies. Thus, insulin detemir offers the promise of an improved tolerability:efficacy ratio in the clinical setting.

摘要

皮下注射后人胰岛素制剂吸收曲线的次优特性促使了更适合糖尿病治疗用途的胰岛素类似物的研发。一个特殊的挑战是设计出长效制剂,使其不同注射之间不会产生过度可变的反应。最近一种取得成功的方法是用脂肪酸对胰岛素分子进行酰化,从而实现与白蛋白的可逆结合。这类药物中首个可用于临床的是地特胰岛素。药理学研究证实,这一原理主要通过延缓吸收来有效延长作用时间。地特胰岛素在小瓶中和注射后的溶解度以及血浆白蛋白结合产生的重要缓冲机制,解释了在重复等血糖钳夹研究中,将地特胰岛素与其他基础胰岛素产品相比较时,观察到的药效学反应个体内变异性显著降低的现象。由于在治疗浓度下白蛋白结合位点与地特胰岛素分子的比例极高,尚未发现与白蛋白结合相关的安全性问题。地特胰岛素分子保留了天然人胰岛素的分子药理学特性,包括代谢和促有丝分裂活性之间的生理平衡。因此,地特胰岛素有望在临床环境中提高耐受性与疗效的比率。

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