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

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.101840v1 319/1/459    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Zamek-Gliszczynski, M. J. Articles by Brouwer, K. L. R. Search for Related Content PubMed PubMed Citation Articles by Zamek-Gliszczynski, M. J. Articles by Brouwer, K. L. R. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH

METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Differential Involvement of Mrp2 (Abcc2) and Bcrp (Abcg2) in Biliary Excretion of 4-Methylumbelliferyl Glucuronide and Sulfate in the Rat

University of North Carolina, School of Pharmacy, Chapel Hill, North Carolina (M.J.Z.-G., X.T., K.N., K.L.R.B.); Pfizer Research Technology Center, Cambridge, Massachusetts (K.A.H.); and GlaxoSmithKline, Inc., Research Triangle Park, North Carolina (J.E.H.)

The hepatic excretion of hydrophilic conjugates, end products of phase II metabolism, is not completely understood. In the present studies, transport mechanism(s) responsible for the biliary excretion of 4-methylumbelliferyl glucuronide (4MUG) and 4-methylumbelliferyl sulfate (4MUS) were studied. Isolated perfused livers (IPLs) from Mrp2-deficient (TR^-) Wistar rats were used to examine the role of Mrp2 in the biliary excretion of 4MUG and 4MUS. After a 30-µmol dose of 4-methylumbelliferone, cumulative biliary excretion of 4MUG was extensive in wild-type rat IPLs (25 ± 3 µmol) but was negligible in TR^- livers (0.4 ± 0.1 µmol); coadministration of the Bcrp and P-glycoprotein inhibitor GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] had no effect on 4MUG biliary excretion in wild-type rat IPLs. In contrast, biliary excretion of 4MUS was partially maintained in Mrp2-deficient rat IPLs. Recovery of 4MUS in bile was 50 to 60% lower in both control TR^- (149 ± 8 nmol) and wild-type IPLs with GF120918 coadministration (176 ± 30 nmol) relative to wild-type control livers (378 ± 37 nmol) and was nearly abolished in TR^- IPLs in the presence of GF120918 (13 ± 8 nmol). These changes were the result of decreased rate constants governing 4MUG and 4MUS biliary excretion. In vitro assays and perfused livers from Bcrp and P-glycoprotein gene-knockout mice indicated that 4MUS did not interact with P-glycoprotein but was transported by Bcrp in a GF120918-sensitive manner. In the rat liver, Mrp2 mediates the biliary excretion of 4MUG, whereas both Mrp2 and Bcrp contribute almost equally to the transport of 4MUS into bile.

Address correspondence to: Dr. Kim L. R. Brouwer, George H. Cocolas Distinguished Professor, University of North Carolina School of Pharmacy, Kerr Hall, CB#7360, Chapel Hill, NC 27599-7360. E-mail: kbrouwer{at}unc.edu

This article has been cited by other articles:

				X. Tian, M. J. Zamek-Gliszczynski, J. Li, A. S. Bridges, K.-i. Nezasa, N. J. Patel, T. J. Raub, and K. L. R. Brouwer Multidrug Resistance-Associated Protein 2 Is Primarily Responsible for the Biliary Excretion of Fexofenadine in Mice Drug Metab. Dispos., January 1, 2008; 36(1): 61 - 64. [Abstract] [Full Text] [PDF]

				E. M. Leslie, G. Ghibellini, K.-i. Nezasa, and K. L.R. Brouwer Biotransformation and transport of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in bile duct-cannulated wild-type and Mrp2/Abcc2-deficient (TR ) Wistar rats Carcinogenesis, December 1, 2007; 28(12): 2650 - 2656. [Abstract] [Full Text] [PDF]

				A. J. Lickteig, C. D. Fisher, L. M. Augustine, L. M. Aleksunes, D. G. Besselsen, A. L. Slitt, J. E. Manautou, and N. J. Cherrington Efflux Transporter Expression and Acetaminophen Metabolite Excretion Are Altered in Rodent Models of Nonalcoholic Fatty Liver Disease Drug Metab. Dispos., October 1, 2007; 35(10): 1970 - 1978. [Abstract] [Full Text] [PDF]

				M. J. Zamek-Gliszczynski, K.-i. Nezasa, X. Tian, A. S. Bridges, K. Lee, M. G. Belinsky, G. D. Kruh, and K. L. R. Brouwer Evaluation of the Role of Multidrug Resistance-Associated Protein (Mrp) 3 and Mrp4 in Hepatic Basolateral Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Abcc3-/- and Abcc4-/- Mice J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1485 - 1491. [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]