![[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}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan; and Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Abstract
The purpose of this study is to examine the significance of efflux transporters in the small intestine to extrude glucuronide (G) and sulfate (S) conjugates into the intestinal lumen. From this standpoint, we performed in situ intestinal perfusion experiments by using Eisai hyperbilirubinemic rats (EHBRs) in which the multidrug resistance protein 2 (Mrp2/Abcc2) is hereditarily defective and breast cancer resistance protein (Bcrp1/Abcg2) knockout mice. The intestinal lumen of EHBRs and Bcrp1 (–/–) mice was perfused with medium containing 4-methylumbelliferone (4MU) and E3040 [6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridilmethyl) benzothiazole] to determine the efflux of metabolites into the outflow. The efflux of E3040-glucuronide (G) in EHBRs was significantly lower compared with that in normal rats. However, no significant difference was observed for the efflux of 4MU-G, 4MU-sulfate (S), and E3040-S between EHBRs and normal rats. In contrast, the efflux of intracellularly formed 4MU-G, 4MU-S, and E3040-G in Bcrp1 (–/–) mice was significantly lower than that in normal mice. Therefore, Bcrp1 has an important role in extruding glucuronide and sulfate conjugates formed in enterocytes into the intestinal lumen, whereas Mrp2 is responsible for the efflux of some glucuronide conjugates.
Address correspondence to: Prof. Yuichi Sugiyama, Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp
This article has been cited by other articles:
|
|
 |
|
  W. Brand, P. A. I. van der Wel, M. J. Rein, D. Barron, G. Williamson, P. J. van Bladeren, and I. M. C. M. Rietjens Metabolism and Transport of the Citrus Flavonoid Hesperetin in Caco-2 Cell Monolayers Drug Metab. Dispos., September 1, 2008; 36(9): 1794 - 1802. [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]
|
|
|
|
 |
|
 C. Naspinski, X. Gu, G.-D. Zhou, S. U. Mertens-Talcott, K. C. Donnelly, and Y. Tian Pregnane X Receptor Protects HepG2 Cells from BaP-Induced DNA Damage Toxicol. Sci., July 1, 2008; 104(1): 67 - 73. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Enokizono, H. Kusuhara, A. Ose, A. H. Schinkel, and Y. Sugiyama Quantitative Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Limiting Brain and Testis Penetration of Xenobiotic Compounds Drug Metab. Dispos., June 1, 2008; 36(6): 995 - 1002. [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]
|
|
|
|
 |
|
 S. Sakamoto, H. Kusuhara, K. Miyata, H. Shimaoka, T. Kanazu, Y. Matsuo, K. Nomura, N. Okamura, S. Hara, K. Horie, et al. Glucuronidation Converting Methyl 1-(3,4-Dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) to a Potent Apical Sodium-Dependent Bile Acid Transporter Inhibitor, Resulting in a Hypocholesterolemic Action J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 610 - 618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamagata, H. Kusuhara, M. Morishita, K. Takayama, H. Benameur, and Y. Sugiyama Improvement of the Oral Drug Absorption of Topotecan through the Inhibition of Intestinal Xenobiotic Efflux Transporter, Breast Cancer Resistance Protein, by Excipients Drug Metab. Dispos., July 1, 2007; 35(7): 1142 - 1148. [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]
|
|
|
|
|
|
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, 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]
|
|
|
|
|
|
E. G. van de Kerkhof, A.-L. B. Ungell, A. K. Sjoberg, M. H. de Jager, C. Hilgendorf, I. A. M. de Graaf, and G. M. M. Groothuis Innovative Methods to Study Human Intestinal Drug Metabolism in Vitro: Precision-Cut Slices Compared with Ussing Chamber Preparations Drug Metab. Dispos., November 1, 2006; 34(11): 1893 - 1902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System. Physiol Rev, October 1, 2006; 86(4): 1179 - 1236. [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]
|
|
 |
 |
 |
|
 |
 |
 |
