QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Patel, N. J. Articles by Brouwer, K. L. R. Search for Related Content PubMed PubMed Citation Articles by Patel, N. J. Articles by Brouwer, K. L. R.

Phenobarbital Alters Hepatic Mrp2 Function by Direct and Indirect Interactions

¹ Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
² Division of Gastroenterology and Hepatology, University Hospital, Gröningen, The Netherlands
³ Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Switzerland

Phenobarbital (PB) treatment impairs the biliary excretion of some organic anions. One mechanism may involve direct competition for biliary excretion by PB and/or a PB metabolite. Alternatively, PB may alter the expression and/or function of hepatic organic anion transport proteins. The role of multidrug resistance-associated protein 2 (Mrp2) in the biliary excretion of PB and metabolites was studied using isolated perfused livers (IPLs) from Wistar and Mrp2-deficient TR^- rats. In normal livers, 4.19 ± 0.53% of the PB dose was recovered in bile as PB metabolites [2.21 ± 0.69% as 5-ethyl-5-(4-OH phenyl) barbituric acid (PBOH)-glucuronide; 1.98 ± 0.09% as PBOH-sulfate]. In TR^- livers, only PBOH-sulfate was recovered in bile (0.35 ± 0.16% of dose) during the 2-h perfusion. Mrp2 message was increased (2.3-fold) by PB pretreatment (80 mg/kg i.p. x 4 days) but decreased to control values after a 48-h washout. Mrp2 protein was increased slightly in PB-treated livers and remained slightly elevated after a 24-h washout, but it was decreased significantly to 62 ±7% of control values after a 48-h washout. The 120-min cumulative biliary excretion of the Mrp2 substrate 5-(and-6)-carboxy-2', 7'-dichlorofluorescein in IPLs from PB-treated rats after a 48-h washout was significantly lower than in vehicle-treated livers (66.3 ± 9.2% versus 83.4 ± 2.4% of the dose, respectively). These data support two mechanisms for impaired biliary excretion of some organic anions by PB treatment: 1) PBOH-glucuronide is a substrate for Mrp2 and may compete with other organic anions for biliary excretion and 2) Mrp2 protein expression and functional capacity is decreased 48 h after PB treatment.

Address correspondence to: Dr. Kim L. R. Brouwer, Division of Drug Delivery and Disposition, School of Pharmacy, CB#7360, Beard Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360. E-mail: kbrouwer{at}unc.edu

This article has been cited by other articles:

				C. Planchamp, A. Hadengue, B. Stieger, J. Bourquin, A. Vonlaufen, J.-L. Frossard, R. Quadri, C. D. Becker, and C. M. Pastor Function of Both Sinusoidal and Canalicular Transporters Controls the Concentration of Organic Anions within Hepatocytes Mol. Pharmacol., April 1, 2007; 71(4): 1089 - 1097. [Abstract] [Full Text] [PDF]

				M. J. Zamek-Gliszczynski, K.-i. Nezasa, X. Tian, J. C. Kalvass, N. J. Patel, T. J. Raub, and K. L. R. Brouwer The Important Role of Bcrp (Abcg2) in the Biliary Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Mice Mol. Pharmacol., December 1, 2006; 70(6): 2127 - 2133. [Abstract] [Full Text] [PDF]

				M. J. Zamek-Gliszczynski, K. A. Hoffmaster, J. E. Humphreys, X. Tian, K.-i. Nezasa, and K. L. R. Brouwer Differential Involvement of Mrp2 (Abcc2) and Bcrp (Abcg2) in Biliary Excretion of 4-Methylumbelliferyl Glucuronide and Sulfate in the Rat J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 459 - 467. [Abstract] [Full Text] [PDF]

				K.-i. Nezasa, X. Tian, M. J. Zamek-Gliszczynski, N. J. Patel, T. J. Raub, and K. L. R. Brouwer ALTERED HEPATOBILIARY DISPOSITION OF 5 (AND 6)-CARBOXY-2',7'-DICHLOROFLUORESCEIN IN Abcg2 (Bcrp1) AND Abcc2 (Mrp2) KNOCKOUT MICE Drug Metab. Dispos., April 1, 2006; 34(4): 718 - 723. [Abstract] [Full Text] [PDF]

				M. J. Zamek-Gliszczynski, K. A. Hoffmaster, X. Tian, R. Zhao, J. W. Polli, J. E. Humphreys, L. O. Webster, A. S. Bridges, J. C. Kalvass, and K. L. R. Brouwer MULTIPLE MECHANISMS ARE INVOLVED IN THE BILIARY EXCRETION OF ACETAMINOPHEN SULFATE IN THE RAT: ROLE OF MRP2 AND BCRP1 Drug Metab. Dispos., August 1, 2005; 33(8): 1158 - 1165. [Abstract] [Full Text] [PDF]

				P. Chandra, B. M. Johnson, P. Zhang, G. M. Pollack, and K. L. R. Brouwer MODULATION OF HEPATIC CANALICULAR OR BASOLATERAL TRANSPORT PROTEINS ALTERS HEPATOBILIARY DISPOSITION OF A MODEL ORGANIC ANION IN THE ISOLATED PERFUSED RAT LIVER Drug Metab. Dispos., August 1, 2005; 33(8): 1238 - 1243. [Abstract] [Full Text] [PDF]