Biomol Ther (Seoul)  
Bosentan and Rifampin Interactions Modulate Influx Transporter and Cytochrome P450 Expression and Activities in Primary Human Hepatocytes
Kyoung-Moon Han1,†,*, Sun-Young Ahn1,†, Hyewon Seo1, Jaesuk Yun1, Hye Jin Cha1, Ji-Soon Shin1, Young-Hoon Kim1, Hyungsoo Kim1, Hye-kyung Park1 and Yong-Moon Lee2
1Pharmacological Research Division, Toxicological and Research Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju 28159, 2College of Pharmacy, Chungbuk National University, Cheongju 28644, Republic of Korea
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The first two authors contributed equally to this work.
Received: July 12, 2016; Revised: September 28, 2016; Accepted: October 27, 2016; Published online: February 6, 2017.
© The Korean Society of Applied Pharmacology. All rights reserved.

The incidence of polypharmacy-which can result in drug-drug interactions-has increased in recent years. Drug-metabolizing enzymes and drug transporters are important polypharmacy modulators. In this study, the effects of bosentan and rifampin on the expression and activities of organic anion-transporting peptide (OATP) and cytochrome P450 (CYP450) 2C9 and CYP3A4 were investigated in vitro. HEK293 cells and primary human hepatocytes overexpressing the target genes were treated with bosentan and various concentrations of rifampin, which decreased the uptake activities of OATP transporters in a dose-dependent manner. In primary human hepatocytes, CYP2C9 and CYP3A4 gene expression and activities decreased upon treatment with 20 μM bosentan+200 μM rifampin. Rifampin also reduced gene expression of OATP1B1, OATP1B3, and OATP2B1 transporter, and inhibited bosentan influx in human hepatocytes at increasing concentrations. These results confirm rifampin- and bosentan-induced interactions between OATP transporters and CYP450.
Keywords: Drug-drug interaction, CYP450, OATP transporters, Rifampin, Bosentan

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