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Titolo:
Intestinal transport and metabolism of glucose-conjugated kyotorphin and cyclic kyotorphin: metabolic degradation is crucial to intestinal absorptionof peptide drugs
Autore:
Mizuma, T; Koyanagi, A; Awazu, S;
Indirizzi:
Tokyo Univ Pharm & Life Sci, Tokyo Yakka Univ, Sch Pharm, Dept Biopharmaceut, Hachioji, Tokyo 19203, Japan Tokyo Univ Pharm & Life Sci Hachioji Tokyo Japan 19203 Tokyo 19203, Japan Tokyo Univ Pharm & Life Sci, Tokyo Yakka Univ, Sch Pharm, Drug Rat Res Ctr, Hachioji, Tokyo 19203, Japan Tokyo Univ Pharm & Life Sci Hachioji Tokyo Japan 19203 Tokyo 19203, Japan
Titolo Testata:
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
fascicolo: 1, volume: 1475, anno: 2000,
pagine: 90 - 98
SICI:
0304-4165(20000601)1475:1<90:ITAMOG>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
RAT-BRAIN; OLIGOPEPTIDE TRANSPORTER; ANALGESIC DIPEPTIDE; ACTIVE ABSORPTION; ENKEPHALIN; AMINOPEPTIDASE; IMPROVEMENT; BESTATIN; ARG;
Keywords:
kyotorphin; intestinal absorption; peptide absorption; metabolism; transport; glucose conjugate; cyclic peptide; kinetic analysis;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
20
Recensione:
Indirizzi per estratti:
Indirizzo: Mizuma, T Tokyo Univ Pharm & Life Sci, Tokyo Yakka Univ, Sch Pharm, Dept Biopharmaceut, 1432-1 Horinouchi, Hachioji, Tokyo 19203, Japan Tokyo Univ Pharm & Life Sci 1432-1 Horinouchi Hachioji Tokyo Japan 19203
Citazione:
T. Mizuma et al., "Intestinal transport and metabolism of glucose-conjugated kyotorphin and cyclic kyotorphin: metabolic degradation is crucial to intestinal absorptionof peptide drugs", BBA-GEN SUB, 1475(1), 2000, pp. 90-98

Abstract

Intestinal transport and metabolism of modified kyotorphin (KTP) were studied in rats. Modified KTPs studied were C-terminally modified KTP with p-aminophenyl-beta-D-glucoside (KTP-pAP beta glc), N-terminally modified KTP-pAP beta glc with t-butyloxycarbonyl group (Boc-KTP-pAP beta glc) and the N- and C-terminally modified KTP by cyclization (cyclic KTP). KTP-pAP beta glewas metabolized at a similar rare to that of KTP, and did not appear on the serosal side. Although Boc-KTP-pAP beta glc was also metabolized, it was more stable than KTP and appeared on the serosal side. Cyclic KTP was also quite stable and appeared on the serosal side. The modified KTPs were evaluated kinetically for absorption consisting of membrane transport and metabolism. Absorption clearance (CLabs) of cyclic KTP, Boc-KTP-pAP beta glc and Boc-KTP was higher than that of KTP (0.247 mu l/min/cm) (Mizuma et al., Biochim. Biophys. Acta 1335 (1997) 111-119), which is the theoretical maximum by complete inhibition of peptidase activity, indicating that derivatization of KTP increases the membrane permeability. Furthermore, the data clearlyshowed that the greater the metabolic clearance (CLmet) of KTP and the KTPderivatives, the lower the absorption clearance (CLabs). These results andfurther simulation study led to the conclusion that metabolic degradation in the intestinal tissues is more critical than membrane permeability (transport) for oral delivery of peptide drugs. Based on the stability of cyclicKTP in serum, this appears to be a good candidate analgesic peptide drug. (C) 2000 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/09/20 alle ore 10:39:29