Peptide YY (PYY) is a 36 amino acid peptide hormone released from enteroendocrine cells. An N-terminally degraded metabolite, PYY3-36, has anorexigenic effects, which makes the PYY system a target for obesity treatment. However, little is known about the kinetics and degrdn. products of PYY. A related peptide, Neuropeptide Y (NPY), may be degraded from the C-terminus. We therefore investigated PYY degrdn. after in vitro incubations in porcine plasma and blood and in vivo by infusing PYY3-36 into multicatheterized pigs (n = 7) (2 pmol/kg/min). Plasma samples were analyzed by region-specific RIAs (RIA) and HPLC anal. A metabolite, corresponding to PYY3-34 was formed after incubation in plasma and blood and during the infusion study. When taking the C-terminal degrdn. into account, the half-life (T1/2) of PYY in blood and plasma amounted to 3.4 ± 0.2 and 6.2 ± 0.2 h, resp. After PYY3-36 infusion in pigs, the peptide was degraded with a T1/2 of 3.6 ± 0.5 min. Significant extn. (20.5 ± 8.0%) compatible with glomerular filtration was obsd. across the kidneys and significant C-terminal degrdn. (26.5 ± 4.8%) was obsd. across the liver. Net balances across the hind limb, splanchnic bed, and lungs were not significantly different from zero. PYY3-34 was unable to activate the Y2 receptor in a transfected cell line. In conclusion, PYY3-36 is extensively degraded to PYY3-34 in the pig, a degrdn. that renders the peptide inactive on the Y2 receptor. Currently used assays are unlikely to be able to detect this degrdn. and therefore measure falsely elevated levels of PYY3-36, leading to underestimation of its physiol. effects.