title: Involvement of the active metabolites in the inhibitory activity of K579 on rat plasma dipeptidyl peptidase IV.
abstract: K579 ((S)-1-[4-methyl-1-(2-pyrimidinyl)-4-piperidylamino]acetyl-2-pyrrolidinecarbonitrile), which is a long-acting and a slow binding dipeptidyl peptidase IV inhibitor, preserved the endogenously secreted active forms of glucagon-like peptide-1, augmented the insulin response and ameliorated the glucose excursion during oral glucose tolerance test in rats. In this study, we measured plasma concentrations of K579 after oral administration to rats. However, K579 was eliminated rapidly from plasma after oral administration to rats. Therefore, we postulated that there are active metabolites of K579 in rat plasma. We investigated the effect of K579 on plasma dipeptidyl peptidase IV activity using bile duct-cannulated rats. The duration of inhibitory action of plasma dipeptidyl peptidase IV after the administration of K579 in bile duct-cannulated rats was shorter than that in sham-operated rats. Moreover, we investigated the effect of bile obtained from K579-treated rat on plasma dipeptidyl peptidase IV activity in normal rats. The bile collected from K579-treated rats exhibited tardive and potent inhibitory activity of normal rat plasma. These results suggest that K579 sustained the duration of inhibitory action of plasma dipeptidyl peptidase IV by the character as a slow-binding inhibitor and, as well, by the presence of metabolites of K579, which exhibit the inhibitory activity of dipeptidyl peptidase IV.
authors.affiliation: Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd. 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka-ken 411-8731, Japan. kotaro.takasaki@kyowa.co.jp
authors.forename: Kotaro
authors.initials: K
authors.lastname: Takasaki
authors.forename: Hidenori
authors.initials: H
authors.lastname: Takada
authors.forename: Takao
authors.initials: T
authors.lastname: Nakajima
authors.forename: Kimihisa
authors.initials: K
authors.lastname: Ueno
authors.forename: Junko
authors.initials: J
authors.lastname: Ushiki
authors.forename: Katsuya
authors.initials: K
authors.lastname: Higo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000502:physiology; D001652:Bile Ducts / Q000601:surgery; D002404:Catheterization; D018819:Dipeptidyl Peptidase 4 / Q000097:blood*; D008297:Male; D009570:Nitriles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: C494668:(S)-1-(4-methyl-1-(2-pyrimidinyl)-4-piperidylamino)acetyl-2-pyrrolidinecarbonitrile; D009570:Nitriles; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4