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Titolo:
IN-VITRO ASSESSMENT OF ORAL DELIVERY FOR HEXAPEPTIDE ENDOTHELIN ANTAGONISTS
Autore:
STEWART BH; REYNER EL; TSE E; HAYES RN; WERNESS S; HE JX; CODY WL; DOHERTY AM;
Indirizzi:
WARNER LAMBERT PARKE DAVIS,PARKE DAVIS PHARMACEUT RES DIV,PHARMACOKINET & DRUG METAB DEPT ANN ARBOR MI 48105 WARNER LAMBERT PARKE DAVIS,PARKE DAVIS PHARMACEUT RES DIV,DEPT CHEM ANN ARBOR MI 48105
Titolo Testata:
Life sciences
fascicolo: 12, volume: 58, anno: 1996,
pagine: 971 - 982
SICI:
0024-3205(1996)58:12<971:IAOODF>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
CELL-LINE CACO-2; DESIGN; PERMEABILITY;
Keywords:
ENDOTHELIN RECEPTOR ANTAGONIST; PD 142893; PD 145065; CACO-2 CELL PERMEABILITY; PEPTIDE STABILITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
14
Recensione:
Indirizzi per estratti:
Citazione:
B.H. Stewart et al., "IN-VITRO ASSESSMENT OF ORAL DELIVERY FOR HEXAPEPTIDE ENDOTHELIN ANTAGONISTS", Life sciences, 58(12), 1996, pp. 971-982

Abstract

Endothelin (ET-1) is a 21-amino acid, vasoconstrictive peptide originally isolated from endothelial cells. It is one member of a class of potent, purportedly paracrine substances that act at receptors in multiple target organs. Antagonists to the receptor subtypes, ET(A) and ET(B), have been designed around the hydrophobic carboxy-terminus of ET-1. The resulting hexapeptides possess low nanomolar receptor affinity, but face formidable challenges to oral delivery, given their peptidic nature. Hence, it was important to discriminate between analogs, as well as to optimize structural features combining binding potency with stability in intestinal fluids and permeability across biological membranes. PD 142893 (Ac-DDip(16)-Leu-Asp-Ile-Ile-Trp(21)) and PD 145065 (Ac-DBhg(16)-Leu-Asp-Ile-Ile-Trp(21)), as well as the N-methyl-isoleucine(20) analogs were studied, where DDip = 3,3-diphenylalanine and DBhg = 10,11-dihydro-5H-dibenzo[a,d]cycloheptene glycine. Analyses were conducted with specific HPLC methods. Permeabilities across CACO-2 cell monolayers ranged from 2.0x10(-4) to 6.3x10(-4) cm/min. The results suggested that these compounds can be absorbed in vivo, based on comparison of permeabilities with those obtained with reference compounds. Much greater differences were observed between the analogs when stabilityhalf-lives were compared after incubation in rat intestinal perfusate. The parent peptides, PD 142893 and PD 145065, were unstable, with half-lives less than 20 min. N-Methylation of Ile(20) resulted in large increases in stability half-lives to greater than 500 min. Enzyme inhibition studies demonstrated the involvement of carboxypeptidase A in production of the primary metabolite, the des-Trp derivative. Identification of the primary metabolite of the parent peptide was made by differential UV scanning at 214/280 nm and mass spectral analyses.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/09/20 alle ore 19:12:47