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Titolo:
THE TOLERABILITY, PHARMACOKINETICS AND LACK OF EFFECT ON PLASMA-CHOLESTEROL OF 447C88, AN ACYLCOA-CHOLESTEROL-ACYL-TRANSFERASE (ACAT) INHIBITOR WITH LOW BIOAVAILABILITY, IN HEALTHY-VOLUNTEERS
Autore:
PECK RW; WIGGS R; POSNER J;
Indirizzi:
WELLCOME RES LABS,DEPT CLIN PHARMACOL,LANGLEY COURT BECKENHAM BR3 3BSKENT ENGLAND
Titolo Testata:
European Journal of Clinical Pharmacology
fascicolo: 3, volume: 49, anno: 1995,
pagine: 243 - 249
SICI:
0031-6970(1995)49:3<243:TTPALO>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
APO-B SECRETION; SERUM-CHOLESTEROL; ACYLTRANSFERASE; METABOLISM; COENZYME; CELLS;
Keywords:
CHOLESTEROL ACYLTRANSFERASE; HYPOCHOLESTEROLEMIC; 447C88; VOLUNTEERS; PHARMACOKINETICS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
26
Recensione:
Indirizzi per estratti:
Citazione:
R.W. Peck et al., "THE TOLERABILITY, PHARMACOKINETICS AND LACK OF EFFECT ON PLASMA-CHOLESTEROL OF 447C88, AN ACYLCOA-CHOLESTEROL-ACYL-TRANSFERASE (ACAT) INHIBITOR WITH LOW BIOAVAILABILITY, IN HEALTHY-VOLUNTEERS", European Journal of Clinical Pharmacology, 49(3), 1995, pp. 243-249

Abstract

447C88 (N-Heptyl-N'-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA:Cholesterol acyltransferase (ACAT) with an IC50 of 10.2 ng . ml(-1) (23 nM). It is poorly absorbed but 5 mg . kg(-1). day(-1) completely abolishes the rise in plasma cholesterol in cholesterol-fed rats. In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n = 8) or placebo (n = 4) withfood in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight East. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n= 8) or placebo (n = 6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food. All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88were unquantifiable after the fasting dose and low after all other doses. Mean C-max and AUC were 1.8 ng . ml(-1) and 9.0 ng . ml-(1) . h after 200 mg rising to 5.4 ng . ml(-1) and 23.8 ng . ml(-1). h respectively after 800 mg; t(1/2) was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- orHDL-cholesterol after dosing with 447C88.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 03/12/20 alle ore 21:38:30