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Titolo:
MECHANISMS OF ENHANCED ORAL AVAILABILITY OF CYP3A4 SUBSTRATES BY GRAPEFRUIT CONSTITUENTS - DECREASED ENTEROCYTE CYP3A4 CONCENTRATION AND MECHANISM-BASED INACTIVATION BY FURANOCOUMARINS
Autore:
SCHMIEDLINREN P; EDWARDS DJ; FITZSIMMONS ME; HE K; LOWN KS; WOSTER PM; RAHMAN A; THUMMEL KE; FISHER JM; HOLLENBERG PF; WATKINS PB;
Indirizzi:
UNIV MICHIGAN,CTR MED,UNIV HOSP,ROOM A7119,POB 0108,1500 E MED CTR DRANN ARBOR MI 48109 UNIV MICHIGAN,MED CTR,DEPT INTERNAL MED ANN ARBOR MI 48109 WAYNE STATE UNIV,DEPT PHARM PRACTICE,COLL PHARM & ALLIED HLTH PROFESSDETROIT MI 48202 WAYNE STATE UNIV,COLL PHARM & ALLIED HLTH PROFESS DETROIT MI 48202 UNIV MICHIGAN,SCH MED,DEPT PHARM ANN ARBOR MI 48109 US FDA,DIV CLIN PHARMACOL,CTR DRUG EVALUAT & RES ROCKVILLE MD 20857 UNIV WASHINGTON,DEPT PHARMACEUT SEATTLE WA 98195
Titolo Testata:
Drug metabolism and disposition
fascicolo: 11, volume: 25, anno: 1997,
pagine: 1228 - 1233
SICI:
0090-9556(1997)25:11<1228:MOEOAO>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
JUICE-FELODIPINE INTERACTION; HUMAN LIVER-MICROSOMES; CYTOCHROME-P450 3A4; INHIBITION; ENZYME; RAT; PHARMACOKINETICS; PURIFICATION; FLAVONOIDS; METABOLISM;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
28
Recensione:
Indirizzi per estratti:
Citazione:
P. Schmiedlinren et al., "MECHANISMS OF ENHANCED ORAL AVAILABILITY OF CYP3A4 SUBSTRATES BY GRAPEFRUIT CONSTITUENTS - DECREASED ENTEROCYTE CYP3A4 CONCENTRATION AND MECHANISM-BASED INACTIVATION BY FURANOCOUMARINS", Drug metabolism and disposition, 25(11), 1997, pp. 1228-1233

Abstract

Grapefruit juice increases the oral availability of a variety of CYP3A4 substrates. It has been shown that recurrent grapefruit juice ingestion results in a loss of CYP3A4 from the small bowel epithelium. We now show that the reduction in intestinal CYP3A4 concentration is rapid; a 47% decrease occurred in a healthy volunteer within 4 hr after consuming grapefruit juice. To identify the specific components of the juice responsible for this effect, we used a recently developed Caco-2 cell culture model of human intestinal epithelium that expresses catalytically active CYP3A4. We found that grapefruit oil and two furanocoumarin constituents (6',7'-dihydroxybergamottin and a closely related dimer) caused a dose-dependent fall in CYP3A4 catalytic activity and immunoreactive CYP3A4 concentration. The effect was selective in that concentrations of CYP1A1 and CYP2D6 did not fall, consistent with previous results obtained in vivo. Assays of various juices confirmed that 6',7'-dihydroxybergamottin is the major furanocoumarin present and, although its concentration Varies significantly among types and brands of grapefruit juice, it is consistently present in concentrations exceeding the IC50 (1 mu M) for loss of midazolam 1'-hydroxylase activity determined in the Caco-2 cells. Studies with recombinant CYP3A4 revealed that 6',7'-dihydroxybergamottin is a mechanism-based inactivator, which supports the idea that loss of CYP3A4 results from accelerated degradation of the enzyme. We conclude that the effect of grapefruit juice on oral availability of CYP3A4 substrates can be largely accounted forby the presence of 6',7'-dihydroxybergamottin although other furanocoumarins probably also contribute.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 24/01/20 alle ore 12:17:34