Metabolism of peptide YY 3–36 in Göttingen mini-pig and rhesus monkey

Abstract Peptide YY 3–36-amide (PYY 3–36 ) is a peptide hormone, which is known to decrease appetite and food-intake by activation of the Y 2 receptor. The current studies were designed to identify the metabolites of PYY 3–36 in mini-pig and rhesus monkey. Plasma samples were analyzed by high resolution LC–MS (and MS/MS) in order to unambiguously identify the metabolites of PYY 3–36 . In summary, the metabolism of PYY 3–36 was similar in mini-pig and rhesus monkey. Several metabolites were identified and PYY 3–34 was identified at the highest levels in plasma. In addition, mini-pigs were also dosed with PYY 1–36 -amide, PYY 3–35 , PYY 3–34 and [ N- methyl 34Q]-PYY 3–36 -amide in order to investigate the mechanisms by which PYY was metabolized. PYY 3–35 was rapidly converted to PYY 3–34 whereas dosing of PYY 3–34 to mini-pigs only showed circulating degradation products at low levels, i.e., PYY 3–34 was metabolically more stable than PYY 3–36 and PYY 3–35 . [ N- methyl 34Q]-PYY 3–36 -amide was hypothesized to be stable toward cleavage between 34Q and 35R and after i.v. administration to mini-pigs, one major cleavage product was identified as [ N- methyl 34Q]-PYY 3–35 . Overall, this showed that cleavage between 35R and 36Y was possible as well as between 34Q and 35R (as shown for PYY 3–35 ), which indicated that metabolism of PYY 3–36 to PYY 3–34 may be a two-step process. PYY 1–36 was also dosed to mini-pigs, which showed that PYY 1–36 was metabolized in the C-terminal as PYY 3–36 . The overall degradation pattern of PYY 1–36 was more complex due to the simultaneous enzymatic degradation in the N-terminal to form PYY 2–34/36 and PYY 3–34/36 . In vitro incubations with heparin stabilized plasma showed that PYY 3–36 was degraded with a half-life of 175 min, whereas incubations with PYY 3–35 (half-life of 6 min) showed a rapid formation of PYY 3–34 . In conclusion, the present studies showed that PYY 3–36 underwent enzymatic degradation in the C-terminal part and that the major circulating metabolite was PYY 3–34 . Furthermore, it may be a sequential two-step process leading to the formation of PYY 3–35 and subsequently the metabolically more stable PYY 3–34 .