Pharmacokinetics and pharmacodynamics of subcutaneously administered PYY3-36 and its analogues in vivo.
Pharmacokinetics and pharmacodynamics of subcutaneously administered PYY3-36 and its analogues in vivo.
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DOI：
10.1016/s0140-6736(15)60343-9
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发表时间：
2015-02-26
期刊：
影响因子：
--
通讯作者：
Bloom, Stephen
中科院分区：
文献类型：
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作者：
Cegla, Jaimini;Cuenco, Joyceline;Bloom, Stephen
背景：肥胖是一种与发病率、死亡率和心理社会影响相关的紧急流行病。控制食欲的关键肠道激素之一是肽酪氨酸-酪氨酸3-36（PYY 3 -36），其循环半衰期仅为8分钟。PYY 3 -36的长效类似物因此具有作为抗肥胖剂的巨大潜力。本研究的目的是研究PYY 3 -36的各种氨基酸修饰对药代动力学及其抑制食物摄入能力的影响。方法：为了研究PYY 3 -36和三种修饰类似物的药代动力学，在大鼠皮下注射肽后，通过颈静脉插管进行血浆肽水平的连续采样（n=4/肽，80 nmol/kg）。为了研究这些肽对食物摄入的影响，皮下注射小鼠（1000 nmol/kg），并在24小时内以定时间隔评估食物摄入（每种肽n=8）。修饰的类似物PYY-AP 3 H的血浆浓度显著高于PYY 3 -36，直至注射后24 h（4 h时p=0·0008，24 h时p=0·0028）。 结果证实，通过添加α-螺旋稳定序列和组氨酸残基对天然肽进行修饰，延长了药代动力学特征。此外，与生理盐水相比，PYY-AP 3 H显著减少食物摄入长达24小时（p
BACKGROUND: Obesity is an emergent epidemic associated with morbidity, mortality, and psychosocial effects. One of the key gut hormones that controls appetite is peptide tyrosine-tyrosine 3-36 (PYY3-36) whose circulating half-life is only 8 min. A long-acting analogue of PYY3-36 would therefore have great potential as an antiobesity agent. The aims of this study were to investigate the effect of various aminoacid modifications of PYY3-36 on pharmacokinetics and their ability to suppress food intake.METHODS: To investigate the pharmacokinetics of PYY3-36 and three modified analogues, serial sampling of plasma peptide levels via cannulation of the jugular vein was performed after subcutaneous injection of the peptide in rats (n=4 per peptide, 80 nmol/kg). To investigate the effect of these peptides on food intake, mice were injected subcutaneously (1000 nmol/kg) and food intake was assessed at timed intervals over 24 h (n=8 per peptide).FINDINGS: One-way ANOVA with post-hoc Dunnett's test was used in which each comparison was with the PYY3-36 or saline group. Plasma concentrations of the modified analogue, PYY-AP3H, were significantly higher than PYY3-36 up to 24 h post injection (p=0·0008 at 4 h, p=0·0028 at 24 h). The results confirm that modification of the native peptide, by addition of an alpha-helix stabilising sequence and histidine residues, lengthens the pharmacokinetic profile. Furthermore, PYY-AP3H significantly reduced food intake for up to 24 h compared with saline (p