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Titolo:
FIRST-PASS METABOLISM OF ONO-5046 PIONYLOXY)PHENYLSULFONYLAMINO]BENZOYL]-AMINOACETIC ACID), A NOVEL ELASTASE INHIBITOR, IN RATS
Autore:
WATANABE F; SATO M; KATO A; MURAKAMI T; HIGASHI Y; YATA N;
Indirizzi:
HIROSHIMA UNIV,SCH MED,INST PHARMACEUT SCI,MINAMI KU,1-2-3 KASUMI HIROSHIMA 734 JAPAN HIROSHIMA UNIV,SCH MED,INST PHARMACEUT SCI,MINAMI KU HIROSHIMA 734 JAPAN SETSUNAN UNIV,FAC PHARMACEUT SCI HIRAKATA OSAKA 57301 JAPAN
Titolo Testata:
Biological & pharmaceutical bulletin
fascicolo: 4, volume: 20, anno: 1997,
pagine: 392 - 396
SICI:
0918-6158(1997)20:4<392:FMOOP>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN NEUTROPHIL ELASTASE; HUMAN-LEUKOCYTE ELASTASE; PROTEINASE-INHIBITORS; DEGRADATION; COLLAGEN; PROTEOLYSIS; DESIGN; POTENT;
Keywords:
ONO-5046; ELASTASE INHIBITOR; FIRST-PASS METABOLISM; INTESTINAL FIRST-PASS METABOLISM; HEPATIC EXTRACTION RATIO; RAT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
16
Recensione:
Indirizzi per estratti:
Citazione:
F. Watanabe et al., "FIRST-PASS METABOLISM OF ONO-5046 PIONYLOXY)PHENYLSULFONYLAMINO]BENZOYL]-AMINOACETIC ACID), A NOVEL ELASTASE INHIBITOR, IN RATS", Biological & pharmaceutical bulletin, 20(4), 1997, pp. 392-396

Abstract

The first-pass metabolism in tile intestine and liver of ONO-5046 opionyloxy)phenylsulfonylamino]benzoyl]aminoacetic acid), a newly synthesized elastase inhibitor, was separately estimated ire rats. When ONO-5046 solution was administered into the whole intestine via the bile duct at a dose of 5 mu mol/rat, the extent of bioavailability was only 1.5%. A small hut significant increase in the bioavailability with an increase in the dose suggested marked first-pass metabolism with a saturable process. Hepatic first-pass metabolism was estimated by determining the hepatic extraction ratio of ONO-5046 after administration intothe portal vein at two different infusion rates (5 mu mol/kg/9 min or5 mu mol/kg/20 s). The extraction ratio was relatively small and constant (about 20%) under 2 different infusion rates of the drug. Intestinal First-pass metabolism was estimated by determining the drug recovery in the mesenteric plasma after administering the drug into the intestinal loop irt situ (mesenteric blood collecting method in situ). Therecovery percentage of ONO-5046 in the mesenteric plasma was small (2.58 +/- 0.04% at a dose of 1 mu mol/rat), and the remaining ONO-5046 recovered in the mesenteric plasma and in the intestinal loop was a metabolite of ONO-5046 (EI-601, (4-hydroxyphenyl)sulfonylamino]benzoyl]aminoacetic acid). Recovery percentage of ONO-5046 in the mesenteric plasma increased significantly with an increase in the dose, although therecovery percentage was still low, even at a higher dose (9.55 +/- 1.17% of dose at a dose of 5 mu mol/rat). These results indicate that the low oral bioavailability of ONO-5046 in vivo is mainly due to the marked intestinal first-pass metabolism, including the metabolism in theintestinal fluid, and the dose-dependent oral bioavailability was derived from the saturable intestinal first-pass metabolism.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 08/08/20 alle ore 07:13:13