title: Possible degradative process of cholecystokinin analogs in rabbit jejunum brush-border membrane vesicles.
abstract: Our recent work on the intestinal metabolism and absorption of cholecystokinin analogs, sulfated C-terminal octapeptide (CCK8; Asp-Tyr(SO(3)H)-Met-Gly-Trp-Met-Asp-Phe(NH(2)) = DY(SO(3)H)MGWMDF(NH(2))) and tetrapeptide (CCK4; Trp-Met-Asp-Phe(NH(2)) = WMDF(NH(2))), was extended to investigate the degradative process of these analogs using rabbit jejunum brush-border membrane vesicles and to find a better enzyme-inhibitor system for intestinal absorption of peptide drugs. Various enzyme inhibitors and a lower pH buffer were applied to discover the major enzyme(s) involved in each process. Metabolic pathways showing degradative processes were proposed for both analogs. The major cleavage site occurs at the W(1)-M(2) for CCK4. At least three metabolic pathways occur independently for CCK8 and appear at peptides bonds between G(4)-W(5), M(6)-D(7), and D(7)-F(NH(2))(8). Many different enzymes of aminopeptidase, endopeptidase, angiotensin-converting enzyme, metalloenzyme, and others were involved in each process. Identification of more specific yet safe enzyme inhibitors and co-administration of various these inhibitors may lead to further enhancement in intestinal peptide absorption when administered orally.
authors.affiliation: College of Pharmacy, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sheng-Fang
authors.initials: SF
authors.lastname: Su
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
authors.forename: Hye J
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D022162:Cytoplasmic Vesicles / Q000378:metabolism*; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005765:Gastrointestinal Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007583:Jejunum / Q000378:metabolism* / Q000648:ultrastructure; D007700:Kinetics; D008871:Microvilli / Q000378:metabolism; D008956:Models, Chemical; D011817:Rabbits; D012844:Sincalide / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013758:Tetragastrin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; D013758:Tetragastrin; D012844:Sincalide