title: Intestinal transport and metabolism of analgesic dipeptide, kyotorphin: rate-limiting factor in intestinal absorption of peptide as drug.
abstract: Intestinal transport and metabolism of kyotorphin (KTP) were studied in rat everted small intestine. KTP on the mucosal side was metabolized completely within 60 min, and any amounts of KTP were not detected on the serosal side. On the other hand, [D-Arg2]-KTP (D-KTP) was stable on the mucosal side to appear on the serosal side. However, N-t-butoxycarbonyl-KTP (Boc-KTP), which was metabolized on the mucosal side faster than KTP, appeared on the serosal side. In intestinal homogenate, KTP was metabolized, and the metabolic clearance (CL(met)) was decreased by peptidase inhibitors, bestatin, o-phenanthrolin and tryptophan hydroxamate. In the presence of these peptidase inhibitors, the absorption clearance (CL(abs)) of KTP was increased. The less the CL(met) of KTP was, the more the CL(abs) of KTP was. Meanwhile, Boc-KTP in intestinal homogenate was stable even in the absence of peptidase inhibitors. The CL(abs) of Boc-KTP was constant irrespective of the stability on the mucosal side. Kinetic analysis by the metabolic inhibition model indicated that the stabilization of KTP in the intestinal tissue could increase the CL(abs) up to 0.247 microl/min per cm, which was as much as the CL(abs) of stable D-KTP. These results led to the conclusion that rate-limiting process in intestinal absorption of KTP is metabolic degradation in intestinal tissue during the absorption.
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mizuma
authors.forename: A
authors.initials: A
authors.lastname: Koyanagi
authors.forename: S
authors.initials: S
authors.lastname: Awazu
mesh_terms: D000700:Analgesics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D004723:Endorphins / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D010618:Phenanthrolines / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000700:Analgesics; D004723:Endorphins; D010618:Phenanthrolines; D011480:Protease Inhibitors; C019448:kyotorphin; C095117:tryptophanhydroxamate; D014364:Tryptophan; D007930:Leucine; C012211:ubenimex; C025205:1,10-phenanthroline