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Titolo:
Elevated alpha-1-acid glycoprotein reduces the volume of distribution and systemic clearance of saquinavir
Autore:
Holladay, JW; Dewey, MJ; Michniak, BB; Wiltshire, H; Halberg, DL; Weigl, P; Liang, ZM; Halifax, K; Lindup, WE; Back, DJ;
Indirizzi:
Univ Arkansas Med Sci, Coll Pharm, Dept Pharmaceut Sci, Little Rock, AR 72205 USA Univ Arkansas Med Sci Little Rock AR USA 72205 Little Rock, AR 72205 USA Univ Arkansas Med Sci, Coll Pharm, Dept Pharm Practice, Little Rock, AR 72205 USA Univ Arkansas Med Sci Little Rock AR USA 72205 Little Rock, AR 72205 USA Univ S Carolina, Dept Biol Sci, Columbia, SC 29208 USA Univ S Carolina Columbia SC USA 29208 pt Biol Sci, Columbia, SC 29208 USA Univ S Carolina, Dept Pharmaceut Sci, Columbia, SC 29208 USA Univ S Carolina Columbia SC USA 29208 rmaceut Sci, Columbia, SC 29208 USA Roche Discovery, Welwyn, England Roche Discovery Welwyn EnglandRoche Discovery, Welwyn, England Roche Labs, Nutley, NJ USA Roche Labs Nutley NJ USARoche Labs, Nutley, NJ USA Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool L69 3BX, Merseyside,England Univ Liverpool Liverpool Merseyside England L69 3BX X, Merseyside,England
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 3, volume: 29, anno: 2001,
pagine: 299 - 303
SICI:
0090-9556(200103)29:3<299:EAGRTV>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
HIV PROTEASE INHIBITORS; TRANSGENIC MICE; ALPHA(1)-ACID GLYCOPROTEIN; ANTIDEPRESSANT ACTIVITY; INDOCYANINE GREEN; BINDING; PLASMA; PHARMACOKINETICS; CLINDAMYCIN; EXPRESSION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Holladay, JW Univ Arkansas Med Sci, Coll Pharm, Dept Pharmaceut Sci, 4301 W Markham St,Slot 522, Little Rock, AR 72205 USA Univ Arkansas Med Sci 4301W Markham St,Slot 522 Little Rock AR USA 72205
Citazione:
J.W. Holladay et al., "Elevated alpha-1-acid glycoprotein reduces the volume of distribution and systemic clearance of saquinavir", DRUG META D, 29(3), 2001, pp. 299-303

Abstract

The purpose of this study was to characterize the relationship between plasma protein binding and the pharmacokinetic disposition of saquinavir during a normal and elevated alpha-1-acid glycoprotein condition. The extent of plasma binding of [C-14]saquinavir to human plasma, human albumin, and human alpha-1-acid glycoprotein was also assessed. Transgenic mice, which overexpress plasma alpha-1-acid glycoprotein, and control mice were given a single intravenous injection of saquinavir (10 mg/kg) and plasma samples were harvested as a function of time. The extent of [C-14] saquinavir (0.5-30 mug/ml) plasma protein binding in each group of mice was determined by ultrafiltration. Plasma saquinavir concentrations from in vivo administration weredetermined by high performance liquid chromatography with tandem mass spectrometry. Saquinavir binding in human plasma and control mouse plasma was similar (approximately 3% unbound). In contrast, the extent of binding was significantly increased in transgenic mice (1.5% unbound). Furthermore, saquinavir was more extensively bound to alpha-1-acid glycoprotein than to albumin (2.1 versus 11.5% unbound). The systemic clearance and volume of distribution of saquinavir were significantly reduced in transgenic mice comparedwith control mice. The results of this study show that alpha-1-acid glycoprotein is the predominant plasma protein to which saquinavir binds. In addition, elevations in plasma alpha-1-acid glycoprotein considerably alter thepharmacokinetic disposition of saquinavir. This is consistent with the observations that systemic exposure to saquinavir in human immunodeficiency virus patients is greater than that in healthy volunteers and that alpha-1-acid glycoprotein levels increase with the degree of HIV infection.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/03/20 alle ore 00:03:34