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Titolo:
IN-VITRO STABILITY AND INTESTINAL-ABSORPTION CHARACTERISTICS OF HEXAPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS
Autore:
HAN HK; STEWART BH; DOHERTY AM; CODY WL; AMIDON GL;
Indirizzi:
UNIV MICHIGAN,COLL PHARM ANN ARBOR MI 48109 UNIV MICHIGAN,COLL PHARM ANN ARBOR MI 48109 PARKE DAVIS PHARMACEUT RES,PHARMACOKINET & DRUG METAB DEPT ANN ARBOR MI 48105 PARKE DAVIS PHARMACEUT RES,DEPT CHEM ANN ARBOR MI 48105
Titolo Testata:
Life sciences (1973)
fascicolo: 18, volume: 63, anno: 1998,
pagine: 1599 - 1609
SICI:
0024-3205(1998)63:18<1599:ISAICO>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
VASOCONSTRICTOR PEPTIDE; BIOLOGICAL-ACTIVITY; CLONING; DESIGN; EXPRESSION; FAMILY;
Keywords:
BILIARY EXCRETION; ENDOTHELIN ANTAGONIST; INTESTINAL ABSORPTION; PD 156252 PROTEASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
22
Recensione:
Indirizzi per estratti:
Citazione:
H.K. Han et al., "IN-VITRO STABILITY AND INTESTINAL-ABSORPTION CHARACTERISTICS OF HEXAPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS", Life sciences (1973), 63(18), 1998, pp. 1599-1609

Abstract

Endothelins are potent vasoconstrictor peptides which have a wide range of tissue distribution and three receptor subtypes (ETA, ETB and ETC). Among the linear hexapeptide ETA / ETB receptor antagonists, PD 145065 (Ac-D-Bhg-L-Leu-L-Asp-L-Ile-L-Ile-L-Trp, Bhg = (10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5-yl)-Gly) and PD 156252 Ac-D-Bhg-L-Leu-L-Asp-L-Ile-(N-methyl)-L-Ile-L-Trp) were selected to evaluate the metabolic stability and intestinal absorption in the absence and/or in the presence of protease inhibitors. In vitro stability of both compounds wasinvestigated in fresh plasma, lumenal perfusate, intestinal and liverhomogenates. PD 156252 was more stable than PD 145065 in intestinal tissue homogenate (63.4 % vs. 20.5 % remaining) and liver homogenate (74.4 % vs. 35.5 % remaining), while both compounds showed relatively good stability in the fresh plasma (94.5 % vs. 86.7 % remaining) and lumenal perfusate (85.8 % vs. 72.3 % remaining). The effect of protease inhibitors on the degradation of PD 145065 and PD 156252 was also investigated. Amastatin, thiorphan, chymostatin and the mixture of these three inhibitors were effective in reducing the degradation of both compounds. The pharmacokinetic parameters of PD 156252, calculated by using a non-ompartmental model, were 6.95 min (terminal half-life), 191 mt(V-ss), and 25.5 mL/min (Cl-tot) after intravenous administration in rats. The intestinal absorption of PD 156252 in rats was evaluated in the absence and/or in the presence of protease inhibitors. The resultsindicate that the major elimination pathway of PD 156252 appears to be the biliary excretion and protease inhibitors increase the intestinal absorption of PD 156252 through increasing metabolic stability.

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Documento generato il 01/04/20 alle ore 16:40:07