JPET Assistant Professor of Medicine (Clinician-Educator)

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Takenaka, O.
Right arrow Articles by Sugiyama, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Takenaka, O.
Right arrow Articles by Sugiyama, Y.

Vol. 280, Issue 2, 948-958, 1997

Carrier-Mediated Active Transport of the Glucuronide and Sulfate of 6-Hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) into Rat Liver: Quantitative Comparison of Permeability in Isolated Hepatocytes, Perfused Liver and Liver in Vivo

Osamu Takenaka, Toru Horie, Hiroshi Suzuki and Yuichi Sugiyama

Tsukuba Research Laboratories, Eisai Co., Ltd., Tokodai, Tsukuba-shi, Ibaraki 300-26, Japan (O.T., T.H.) and Faculty of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan (H.S., Y.S.)

The hepatic uptake of glucuronic acid and sulfate conjugates of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040), a dual inhibitor of 5-lipoxygenase and thromboxane A2 synthetase, was investigated in rats. The biliary excretion clearance values for the glucuronide and the sulfate, obtained after i.v. administration of E3040, were similar and corresponded to approximately 30% of the hepatic blood flow rate. The influx clearance values of E3040 conjugates in the presence of 3% bovine serum albumin, measured by a multiple indicator dilution method in the perfused liver, were 1.20 ml/min/g liver for the glucuronide and 0.74 ml/min/g liver for the sulfate, which were twice and equal to the normal hepatic plasma flow rate, respectively, which suggests the presence of an efficient transport system(s). The uptake of E3040 conjugates into the isolated hepatocytes is mediated by Na+-independent active transport system(s), which is inhibited by dibromosulfophthalein and bile acids. The uptake for the sulfate had high-affinity and high-capacity transport activity (Km = 25 µM; Vmax = 7.8 nmol/min/106 cells) compared with that for the glucuronide (Km = 59 µM; Vmax = 2.2 nmol/min/106 cells). The uptakes of E3040 conjugates (glucuronide, sulfate) exhibited a mutual competitive inhibition. It is suggested that both conjugates share a multispecific organic anion transporter located on the sinusoidal membrane.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
N. Mizuno, M. Suzuki, H. Kusuhara, H. Suzuki, K. Takeuchi, T. Niwa, J. W. Jonker, and Y. Sugiyama
IMPAIRED RENAL EXCRETION OF 6-HYDROXY-5,7-DIMETHYL-2-METHYLAMINO-4-(3-PYRIDYLMETHYL) BENZOTHIAZOLE (E3040) SULFATE IN BREAST CANCER RESISTANCE PROTEIN (BCRP1/ABCG2) KNOCKOUT MICE
Drug Metab. Dispos., September 1, 2004; 32(9): 898 - 901.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
L. Sabordo, B. C. Sallustio, A. M. Evans, and R. L. Nation
Hepatic Disposition of the Acyl Glucuronide 1-O-Gemfibrozil-beta -D-glucuronide: Effects of Clofibric Acid, Acetaminophen, and Acetaminophen Glucuronide
J. Pharmacol. Exp. Ther., October 1, 2000; 295(1): 44 - 50.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
H. Kouzuki, H. Suzuki, B. Stieger, P. J. Meier, and Y. Sugiyama
Characterization of the Transport Properties of Organic Anion Transporting Polypeptide 1 (oatp1) and Na+/Taurocholate Cotransporting Polypeptide (Ntcp): Comparative Studies on the Inhibitory Effect of their Possible Substrates in Hepatocytes and cDNA-Transfected COS-7 Cells
J. Pharmacol. Exp. Ther., February 1, 2000; 292(2): 505 - 511.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
L. Sabordo, B. C. Sallustio, A. M. Evans, and R. L. Nation
Hepatic Disposition of the Acyl Glucuronide1-O-Gemfibrozil-beta -D-Glucuronide: Effects of Dibromosulfophthalein on Membrane Transport and Aglycone Formation
J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 414 - 420.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
H. Kouzuki, H. Suzuki, K. Ito, R. Ohashi, and Y. Sugiyama
Contribution of Organic Anion Transporting Polypeptide to Uptake of Its Possible Substrates into Rat Hepatocytes
J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 627 - 634.
[Abstract] [Full Text]

Home page
 Drug Metab. Dispos.Home page
K. J. Dix, D. P. Coleman, and A. R. Jeffcoat
Comparative Metabolism and Disposition of Gemfibrozil in Male and Female Sprague-Dawley Rats and Syrian golden Hamsters
Drug Metab. Dispos., January 1, 1999; 27(1): 138 - 146.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
H. Ishizuka, K. Konno, H. Naganuma, K. Nishimura, H. Kouzuki, H. Suzuki, B. Stieger, P. J. Meier, and Y. Sugiyama
Transport of Temocaprilat into Rat Hepatocytes: Role of Organic Anion Transporting Polypeptide
J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 37 - 42.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
H. Kouzuki, H. Suzuki, K. Ito, R. Ohashi, and Y. Sugiyama
Contribution of Sodium Taurocholate Co-Transporting Polypeptide to the Uptake of Its Possible Substrates Into Rat Hepatocytes
J. Pharmacol. Exp. Ther., August 1, 1998; 286(2): 1043 - 1050.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1997 by the American Society for Pharmacology and Experimental Therapeutics.