Pharmacokinetics and pharmacodynamics of subcutaneously administered PYY3-36 and its analogues in vivo

Jaimini Cegla; Joyceline Cuenco; James Minnion; Samar Ghourab; Klara Hostomska; Tricia Tan; Stephen Bloom

doi:10.1016/S0140-6736(15)60343-9

Pharmacokinetics and pharmacodynamics of subcutaneously administered PYY3-36 and its analogues in vivo

Lancet. 2015 Feb 26:385 Suppl 1:S28. doi: 10.1016/S0140-6736(15)60343-9.

Authors

Jaimini Cegla¹, Joyceline Cuenco², James Minnion², Samar Ghourab², Klara Hostomska², Tricia Tan², Stephen Bloom²

Affiliations

¹ Division of Diabetes, Endocrinology & Metabolism, Imperial College London, London, UK. Electronic address: [email protected].
² Division of Diabetes, Endocrinology & Metabolism, Imperial College London, London, UK.

PMID: 26312850
DOI: 10.1016/S0140-6736(15)60343-9

Abstract

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 α-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<0·0001) and native PYY3-36 (p<0·0001).

Interpretation: The rationally designed analogue, PYY-AP3H, has potential as a once-a-day subcutaneously administered preparation for the treatment of obesity.

Funding: UK Medical Research Council, Biotechnology and Biological Sciences Research Council, National Institute for Health Research (NIHR), an Integrative Mammalian Biology (IMB) Capacity Building award, an FP7-HEALTH-2009-241592 EuroCHIP grant, NIHR Imperial Biomedical Research Centre Funding Scheme.

Abstract

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