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Drug Metabolism and Disposition Fast Forward
First published on June 6, 2007; DOI: 10.1124/dmd.107.015842

0090-9556/07/3509-1580-1586$20.00
DMD 35:1580-1586, 2007

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Effect of Pregnane X Receptor Ligand on Pharmacokinetics of Substrates of Organic Cation Transporter Oct1 in Rats

Tomoji Maeda, Masanobu Oyabu, Takafumi Yotsumoto, Ryunosuke Higashi, Kiyoshi Nagata, Yasushi Yamazoe, and Ikumi Tamai

Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan (T.M., M.O., T.Y., R.H., I.T.); Department of Environmental and Health Science, Tohoku Pharmaceutical University, Sendai, Japan (K.N.); and Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.Y.)

Because rat organic cation transporter 1 (Oct1, SLC22a1) is expressed mainly in the liver and mediates drug transport, its activity may determine the hepatic handling of cationic drugs. Here, we studied the regulation mechanism of the expression of Oct1, focusing on the nuclear receptors. In vitro studies using cultured hepatocytes indicated that expression of Oct1 was up-regulated by treatment with pregnenolone-16{alpha}-carbonitrile (PCN) and by overexpression of rat pregnane X receptor (PXR). In addition, isolated rat hepatocytes exhibited an increase of 1-methyl-4-phenylpyridinium (MPP+) uptake on treatment with PCN. When rats were subcutaneously administered PCN, an increase of biliary excretion clearance and distribution volume was observed for drugs such as MPP+, metformin, and tetraethylammonium, although the effects on pharmacokinetic parameters were variable among the tested drugs. In addition, the expression of Oct2 in kidney was increased by treatment with PCN. Thus, PXR ligands appear to regulate the expression of organic cation transporters in rats and thereby to influence the pharmacokinetic properties of cationic drugs. Because PXR ligands include various clinically used drugs, alterations of hepatic drug handling may arise from interactions between cationic drugs that are substrates of Oct1 and ligands of PXR.

Address correspondence to: Dr. Ikumi Tamai, Prof., Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba, 278-8510, Japan. E-mail: tamai{at}rs.noda.tus.ac.jp






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