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Titolo:
IN-VIVO METABOLISM-BASED DISCOVERY OF A POTENT CHOLESTEROL ABSORPTIONINHIBITOR, SCH58235, IN THE RAT AND RHESUS-MONKEY THROUGH THE IDENTIFICATION OF THE ACTIVE METABOLITES OF SCH48461
Autore:
VANHEEK M; FRANCE CF; COMPTON DS; MCLEOD RL; YUMIBE NP; ALTON KB; SYBERTZ EJ; DAVIS HR;
Indirizzi:
SCHERING PLOUGH CORP,RES INST,DEPT CNS & CARDIOVASC RES,2015 GALLOPING HILL RD KENILWORTH NJ 07033 SCHERING PLOUGH CORP,RES INST,DEPT ALLERGY KENILWORTH NJ 07033 SCHERING PLOUGH CORP,RES INST,DEPT DRUG METAB & PHARMACOKINET KENILWORTH NJ 07033
Titolo Testata:
The Journal of pharmacology and experimental therapeutics
fascicolo: 1, volume: 283, anno: 1997,
pagine: 157 - 163
SICI:
0022-3565(1997)283:1<157:IMDOAP>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
COA REDUCTASE INHIBITORS; HYPERCHOLESTEROLEMIA; SCH-48461; DIETARY; GENE; MICE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
21
Recensione:
Indirizzi per estratti:
Citazione:
M. Vanheek et al., "IN-VIVO METABOLISM-BASED DISCOVERY OF A POTENT CHOLESTEROL ABSORPTIONINHIBITOR, SCH58235, IN THE RAT AND RHESUS-MONKEY THROUGH THE IDENTIFICATION OF THE ACTIVE METABOLITES OF SCH48461", The Journal of pharmacology and experimental therapeutics, 283(1), 1997, pp. 157-163

Abstract

SCH48461 is a selective and highly potent inhibitor of cholesterol absorption. In rats, SCH48461 is rapidly and completely metabolized in the first pass through the body. To compare the activity of the metabolites of SCH48461 with SCH48461 itself, an intestinally cannulated, bile duct-cannulated rat model for cholesterol absorption was developed. SCH48461 inhibited the absorption of cholesterol by 70%, whereas bile containing the metabolites of SCH48461 (henceforth, ''metabolite bile'') inhibited the absorption by greater than 95%. Very little of the recovered radioactive dose of SCH48461 was located in the intestinal lumen (7%) or wall (4%), whereas 85% appeared in bile. However, in rats treated with metabolite bile, 62% of the dose remained in the lumen, 13% was associated with the wall and only 24% reappeared in bile, which suggests that the activity of the metabolite bile may be related to its higher retention in the intestinal wall. Rats treated with metabolite bile had 64% and 84% less drug-related radioactivity in their plasmaand livers, respectively, compared with animals treated with SCH48461, which indicates that the metabolites are systemically less availablethan SCH48461. The metabolites in bile were separated by high-performance liquid chromatography; the most active fraction in the bile duct-cannulated rat model was identified by mass spectrometry as the glucuronide of the C4-phenol of SCH48461. The other fractions had moderate or no activity, Through the identification of the most active biliary metabolites of SCH48461 in the rat, we have discovered SCH58235, a novel cholesterol absorption inhibitor which is 400 times more potent thanSCH48461 in the cholesterol-fed rhesus monkey.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 16/01/21 alle ore 23:44:12