![[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}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Until recently, it was generally believed that the transport of various organic anions across the bile canalicular membrane was mainly mediated by multidrug resistance-associated protein 2 (MRP2/ABCC2). However, a number of new reports have shown that some organic anions are also substrates of multidrug resistance 1 (MDR1/ABCB1) and/or breast cancer resistance protein (BCRP/ABCG2), implying MDR1 and BCRP could also be involved in the biliary excretion of organic anions in humans. In the present study, we constructed new double-transfected Madin-Darby canine kidney II (MDCKII) cells expressing organic anion-transporting polypeptide 1B1 (OATP1B1)/MDR1 and OATP1B1/BCRP, and we investigated the transcellular transport of four kinds of organic anions, estradiol-17
-D-glucuronide (EG), estrone-3-sulfate (ES), pravastatin (PRA), and cerivastatin (CER), to identify which efflux transporters mediate the biliary excretion of compounds using double-transfected cells. We observed the vectorial transport of EG and ES in all the double transfectants. MRP2 showed the highest efflux clearance of EG among these efflux transporters, whereas BCRP-mediated clearance of ES was the highest in these double transfectants. In addition, two kinds of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, CER and PRA, were also substrates of all these efflux transporters. The rank order of the efflux clearance of PRA mediated by each transporter was the same as that of EG, whereas the contribution of MDR1 to the efflux of CER was relatively greater than for PRA. This experimental system is very useful for identifying which transporters are involved in the biliary excretion of organic anions that cannot easily penetrate the plasma membrane.
Address correspondence to: Dr. 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:
|
|
 |
|
  M. Hirouchi, H. Kusuhara, R. Onuki, B. W. Ogilvie, A. Parkinson, and Y. Sugiyama Construction of Triple-Transfected Cells [Organic Anion-Transporting Polypeptide (OATP) 1B1/Multidrug Resistance-Associated Protein (MRP) 2/MRP3 and OATP1B1/MRP2/MRP4] for Analysis of the Sinusoidal Function of MRP3 and MRP4 Drug Metab. Dispos., October 1, 2009; 37(10): 2103 - 2111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-i. Umehara, N. Shirai, T. Iwatsubo, K. Noguchi, T. Usui, and H. Kamimura Identification of Human Metabolites of (-)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a Novel If Channel Inhibitor, and Investigation of the Transporter-Mediated Renal and Hepatic Excretion of These Metabolites Drug Metab. Dispos., August 1, 2009; 37(8): 1646 - 1657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhang, J. Li, S. M. Allen, E. A. Weiskircher, Y. Huang, R. A. George, R. G. Fong, A. Owen, and I. J. Hidalgo Silencing the Breast Cancer Resistance Protein Expression and Function in Caco-2 Cells Using Lentiviral Vector-Based Short Hairpin RNA Drug Metab. Dispos., April 1, 2009; 37(4): 737 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kitamura, K. Maeda, Y. Wang, and Y. Sugiyama Involvement of Multiple Transporters in the Hepatobiliary Transport of Rosuvastatin Drug Metab. Dispos., October 1, 2008; 36(10): 2014 - 2023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Verhulst, R. Sayer, M. E. De Broe, P. C. D'Haese, and C. D. A. Brown Human Proximal Tubular Epithelium Actively Secretes but Does Not Retain Rosuvastatin Mol. Pharmacol., October 1, 2008; 74(4): 1084 - 1091. [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]
|
|
|
|
|
|
K.-i. Umehara, M. Iwai, Y. Adachi, T. Iwatsubo, T. Usui, and H. Kamimura Hepatic Uptake and Excretion of (-)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a Novel If Channel Inhibitor, in Rats and Humans Drug Metab. Dispos., June 1, 2008; 36(6): 1030 - 1038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Matsushima, K. Maeda, H. Hayashi, Y. Debori, A. H. Schinkel, J. D. Schuetz, H. Kusuhara, and Y. Sugiyama Involvement of Multiple Efflux Transporters in Hepatic Disposition of Fexofenadine Mol. Pharmacol., May 1, 2008; 73(5): 1474 - 1483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Matsushima, K. Maeda, N. Ishiguro, T. Igarashi, and Y. Sugiyama Investigation of the Inhibitory Effects of Various Drugs on the Hepatic Uptake of Fexofenadine in Humans Drug Metab. Dispos., April 1, 2008; 36(4): 663 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ishiguro, K. Maeda, A. Saito, W. Kishimoto, S. Matsushima, T. Ebner, W. Roth, T. Igarashi, and Y. Sugiyama Establishment of a Set of Double Transfectants Coexpressing Organic Anion Transporting Polypeptide 1B3 and Hepatic Efflux Transporters for the Characterization of the Hepatobiliary Transport of Telmisartan Acylglucuronide Drug Metab. Dispos., April 1, 2008; 36(4): 796 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Inoue, Y. Nakai, S. Ueda, S. Kamigaso, K.-y. Ohta, M. Hatakeyama, Y. Hayashi, M. Otagiri, and H. Yuasa Functional characterization of PCFT/HCP1 as the molecular entity of the carrier-mediated intestinal folate transport system in the rat model Am J Physiol Gastrointest Liver Physiol, March 1, 2008; 294(3): G660 - G668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yamada, K. Maeda, E. Kamiyama, D. Sugiyama, T. Kondo, Y. Shiroyanagi, H. Nakazawa, T. Okano, M. Adachi, J. D. Schuetz, et al. Multiple Human Isoforms of Drug Transporters Contribute to the Hepatic and Renal Transport of Olmesartan, a Selective Antagonist of the Angiotensin II AT1-Receptor Drug Metab. Dispos., December 1, 2007; 35(12): 2166 - 2176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ando, H. Kusuhara, G. Merino, A. I. Alvarez, A. H. Schinkel, and Y. Sugiyama Involvement of Breast Cancer Resistance Protein (ABCG2) in the Biliary Excretion Mechanism of Fluoroquinolones Drug Metab. Dispos., October 1, 2007; 35(10): 1873 - 1879. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Enokizono, H. Kusuhara, and Y. Sugiyama Effect of Breast Cancer Resistance Protein (Bcrp/Abcg2) on the Disposition of Phytoestrogens Mol. Pharmacol., October 1, 2007; 72(4): 967 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Lai, L. Xing, G. I. Poda, and Y. Hu Structure-Activity Relationships for Interaction with Multidrug Resistance Protein 2 (ABCC2/MRP2): The Role of Torsion Angle for a Series of Biphenyl-Substituted Heterocycles Drug Metab. Dispos., June 1, 2007; 35(6): 937 - 945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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. Hirano, K. Maeda, Y. Shitara, and Y. Sugiyama DRUG-DRUG INTERACTION BETWEEN PITAVASTATIN AND VARIOUS DRUGS VIA OATP1B1 Drug Metab. Dispos., July 1, 2006; 34(7): 1229 - 1236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Yamashiro, K. Maeda, M. Hirouchi, Y. Adachi, Z. Hu, and Y. Sugiyama INVOLVEMENT OF TRANSPORTERS IN THE HEPATIC UPTAKE AND BILIARY EXCRETION OF VALSARTAN, A SELECTIVE ANTAGONIST OF THE ANGIOTENSIN II AT1-RECEPTOR, IN HUMANS Drug Metab. Dispos., July 1, 2006; 34(7): 1247 - 1254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Liu, Y. Cui, A. Y. Chung, Y. Shitara, Y. Sugiyama, D. Keppler, and K. S. Pang Vectorial Transport of Enalapril by Oatp1a1/Mrp2 and OATP1B1 and OATP1B3/MRP2 in Rat and Human Livers J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 395 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Huang, Y. Wang, and S. Grimm ATP-DEPENDENT TRANSPORT OF ROSUVASTATIN IN MEMBRANE VESICLES EXPRESSING BREAST CANCER RESISTANCE PROTEIN Drug Metab. Dispos., May 1, 2006; 34(5): 738 - 742. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
