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Titolo:
Altered hepatobiliary disposition of acetaminophen glucuronide in isolatedperfused livers from multidrug resistance-associated protein 2-deficient TR- rats
Autore:
Xiong, H; Turner, KC; Ward, ES; Jansen, PLM; Brouwer, KLR;
Indirizzi:
Univ N Carolina, Sch Pharm, Div Drug Delivery & Disposit, Chapel Hill, NC 27599 USA Univ N Carolina Chapel Hill NC USA 27599 posit, Chapel Hill, NC 27599 USA Univ N Carolina, Sch Med, Curriculum Toxicol, Chapel Hill, NC 27599 USA Univ N Carolina Chapel Hill NC USA 27599 xicol, Chapel Hill, NC 27599 USA Univ Groningen Hosp, Div Gastroenterol & Hepatol, Groningen, Netherlands Univ Groningen Hosp Groningen Netherlands patol, Groningen, Netherlands
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 2, volume: 295, anno: 2000,
pagine: 512 - 518
SICI:
0022-3565(200011)295:2<512:AHDOAG>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
PLASMA-MEMBRANE VESICLES; ATP-DEPENDENT TRANSPORT; IMPAIRED BILIARY-EXCRETION; GLUTATHIONE S-CONJUGATE; PHENOBARBITAL PRETREATMENT; MUTANT RATS; HYPERBILIRUBINEMIA; MECHANISMS; PHARMACOKINETICS; TAUROCHOLATE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Brouwer, KLR Univ N Carolina, Sch Pharm, Div Drug Delivery & Disposit, CB 7360,28 BeardHall, Chapel Hill, NC 27599 USA Univ N Carolina CB 7360,28 Beard Hall Chapel Hill NC USA 27599
Citazione:
H. Xiong et al., "Altered hepatobiliary disposition of acetaminophen glucuronide in isolatedperfused livers from multidrug resistance-associated protein 2-deficient TR- rats", J PHARM EXP, 295(2), 2000, pp. 512-518

Abstract

Previous studies have demonstrated that phenobarbital treatment impairs the biliary excretion of acetaminophen glucuronide (AG), although the transport system(s) responsible for AG excretion into bile has not been identified. Initial studies in rat canalicular liver plasma membrane vesicles indicated that AG uptake was stimulated modestly by ATP, but not by membrane potential, HCO3-, or pH gradients. To examine the role of the ATP-dependent canalicular transporter multidrug resistance-associated protein 2 (Mrp2)/canalicular multispecific organic anion transporter (cMOAT) in the biliary excretion of AG, the hepatobiliary disposition of acetaminophen, AG, and acetaminophen sulfate (AS) was examined in isolated perfused livers from control and TR- (Mrp2-deficient) Wistar rats. Mean bile flow in TR- livers was similar to0.3 mul/min/g of liver (similar to4-fold lower than control). AG biliary excretion was decreased (>300-fold) to negligible levels in TR- rat livers, indicating that AG is an Mrp2 substrate. Similarly, AS biliary excretionin TR- livers was decreased (similar to5-fold); however, concentrations were still measurable, suggesting that multiple mechanisms, including Mrp2-mediated active transport, may be involved in AS biliary excretion. AG and ASperfusate concentrations were significantly higher in livers from TR- compared with control rats. Pharmacokinetic modeling of the data revealed that the rate constant for basolateral egress of AG increased significantly from0.028 to 0.206 min(-1), consistent with up-regulation of a basolateral organic anion transporter in Mrp2-deficient rat livers. In conclusion, these data indicate that AG biliary excretion is mediated by Mrp2, and clearly demonstrate that substrate disposition may be influenced by alterations in complementary transport systems in transport-deficient animals.

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Documento generato il 25/11/20 alle ore 09:13:47