PT  - JOURNAL ARTICLE
AU  - Tomoji Maeda
AU  - Masanobu Oyabu
AU  - Takafumi Yotsumoto
AU  - Ryunosuke Higashi
AU  - Kiyoshi Nagata
AU  - Yasushi Yamazoe
AU  - Ikumi Tamai
TI  - Effect of Pregnane X Receptor Ligand on Pharmacokinetics of Substrates of Organic Cation Transporter Oct1 in Rats
AID  - 10.1124/dmd.107.015842
DP  - 2007 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1580--1586
VI  - 35
IP  - 9
4099  - http://dmd.aspetjournals.org/content/35/9/1580.short
4100  - http://dmd.aspetjournals.org/content/35/9/1580.full
SO  - Drug Metab Dispos2007 Sep 01; 35
AB  - 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-16α-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. The American Society for Pharmacology and Experimental Therapeutics