![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication May 22, 2006.
Revised August 19, 2006.
Accepted for publication September 6, 2006.
The role of Mrp2, Bcrp, and P-glycoprotein in the biliary excretion of acetaminophen sulfate (AS) and glucuronide (AG), 4-methylumbelliferyl sulfate (4MUS) and glucuronide (4MUG), and harmol sulfate (HS) and glucuronide (HG) was studied in Abcc2(-/-), Abcg2(-/-), and Abcb1a(-/-)/Abcb1b(-/-) mouse livers perfused with the respective parent compounds using a cassette dosing approach. Biliary clearance of the sulfate conjugates was significantly decreased in Bcrp-deficient mouse livers, resulting in negligible biliary excretion of AS, 4MUS, and HS. Interestingly, the most profound decrease in the biliary clearance of the glucuronide conjugates was observed in Bcrp-deficient mouse livers, although the biliary clearance of 4MUG was also ~35% lower in Mrp2-deficient mouse livers. As expected, biliary excretion of conjugates was not impaired in P-glycoprotein-deficient livers. An appreciable increase in perfusate recovery due to a shift in the directionality of metabolite excretion, from bile to perfusate, was noted in knockout mice only for conjugates whose biliary clearance constituted an appreciable (
37%) fraction of total hepatic excretory clearance (i.e. 4MUS, HG, and HS). Biliary clearance of AG, AS, and 4MUG constituted a small fraction of total hepatic excretory clearance, so an appreciable increase in perfusate recovery of these metabolites was not observed in knockout mice despite markedly decreased biliary excretion. Unlike in rats, where sulfate and glucuronide conjugates were excreted into bile predominantly by Mrp2, mouse Bcrp mediated the biliary excretion of sulfate metabolites, and also played a major role in the biliary excretion of the glucuronide metabolites, with some minor contribution from mouse Mrp2.
Key words:
MDR/p-Glycoprotein, Organic anion, Phase II enzymes, Sulfotransferases, UDP-glucuronyltransferases
This article has been cited by other articles:
|
|
 |
|
  J. K. Lee, K. Abe, A. S. Bridges, N. J. Patel, T. J. Raub, G. M. Pollack, and K. L. R. Brouwer Sex-Dependent Disposition of Acetaminophen Sulfate and Glucuronide in the in Situ Perfused Mouse Liver Drug Metab. Dispos., September 1, 2009; 37(9): 1916 - 1921. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, Y. Byun, Y. R. Ren, J. O. Liu, J. Laterra, and M. G. Pomper Identification of Inhibitors of ABCG2 by a Bioluminescence Imaging-Based High-Throughput Assay Cancer Res., July 15, 2009; 69(14): 5867 - 5875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Kis, T Nagy, M Jani, E Molnar, J Janossy, O Ujhellyi, K Nemet, K Heredi-Szabo, and P Krajcsi Leflunomide and its metabolite A771726 are high affinity substrates of BCRP: implications for drug resistance Ann Rheum Dis, July 1, 2009; 68(7): 1201 - 1207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zhao, T. J. Raub, G. A. Sawada, S. C. Kasper, J. A. Bacon, A. S. Bridges, and G. M. Pollack Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier Drug Metab. Dispos., June 1, 2009; 37(6): 1251 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Zamek-Gliszczynski, J. C. Kalvass, G. M. Pollack, and K. L. R. Brouwer Relationship between Drug/Metabolite Exposure and Impairment of Excretory Transport Function Drug Metab. Dispos., February 1, 2009; 37(2): 386 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. He, M. W. Lago, R. A. Iyer, W.-C. Shyu, W. G. Humphreys, and L. J. Christopher Lacteal Secretion, Fetal and Maternal Tissue Distribution of Dasatinib in Rats Drug Metab. Dispos., December 1, 2008; 36(12): 2564 - 2570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Zamek-Gliszczynski, K. A. Hoffmaster, K.-i. Nezasa, and K. L. R. Brouwer Apparent Differences in Mechanisms of Harmol Sulfate Biliary Excretion in Mice and Rats Drug Metab. Dispos., November 1, 2008; 36(11): 2156 - 2158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Garland, K. M. Abildskov, T.-w. Kiu, S. S. Daniel, P. Weldy, and R. I. Stark Placental Transfer and Fetal Elimination of Morphine-3-{beta}-glucuronide in the Pregnant Baboon Drug Metab. Dispos., September 1, 2008; 36(9): 1859 - 1868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sakamoto, H. Kusuhara, K. Horie, K. Takahashi, T. Baba, J. Ishizaki, and Y. Sugiyama Identification of the Transporters Involved in the Hepatobiliary Transport and Intestinal Efflux of Methyl 1-(3,4-Dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) Glucuronide, a Pharmacologically Active Metabolite of S-8921 Drug Metab. Dispos., August 1, 2008; 36(8): 1553 - 1561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kato, S. Takahara, S. Kato, Y. Kubo, Y. Sai, I. Tamai, H. Yabuuchi, and A. Tsuji Involvement of Multidrug Resistance-Associated Protein 2 (Abcc2) in Molecular Weight-Dependent Biliary Excretion of {beta}-Lactam Antibiotics Drug Metab. Dispos., June 1, 2008; 36(6): 1088 - 1096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. M. Villanueva, M. L. Ruiz, C. I. Ghanem, M. G. Luquita, V. A. Catania, and A. D. Mottino Hepatic Synthesis and Urinary Elimination of Acetaminophen Glucuronide Are Exacerbated in Bile Duct-Ligated Rats Drug Metab. Dispos., March 1, 2008; 36(3): 475 - 480. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Klaassen and H. Lu Xenobiotic Transporters: Ascribing Function from Gene Knockout and Mutation Studies Toxicol. Sci., February 1, 2008; 101(2): 186 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Lu and C. Klaassen Gender Differences in mRNA Expression of ATP-Binding Cassette Efflux and Bile Acid Transporters in Kidney, Liver, and Intestine of 5/6 Nephrectomized Rats Drug Metab. Dispos., January 1, 2008; 36(1): 16 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. Enokizono, H. Kusuhara, and Y. Sugiyama Regional Expression and Activity of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Mouse Intestine: Overlapping Distribution with Sulfotransferases Drug Metab. Dispos., June 1, 2007; 35(6): 922 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Pal, D. Mehn, E. Molnar, S. Gedey, P. Meszaros, T. Nagy, H. Glavinas, T. Janaky, O. von Richter, G. Bathori, et al. Cholesterol Potentiates ABCG2 Activity in a Heterologous Expression System: Improved in Vitro Model to Study Function of Human ABCG2 J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1085 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Enokizono, H. Kusuhara, and Y. Sugiyama Involvement of Breast Cancer Resistance Protein (BCRP/ABCG2) in the Biliary Excretion and Intestinal Efflux of Troglitazone Sulfate, the Major Metabolite of Troglitazone with a Cholestatic Effect Drug Metab. Dispos., February 1, 2007; 35(2): 209 - 214. [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]
|
|
 |
 |
 |
|
 |
 |
 |
