Biomol Ther.  2017 May;25(3):288-295. 10.4062/biomolther.2016.153.

Bosentan and Rifampin Interactions Modulate Influx Transporter and Cytochrome P450 Expression and Activities in Primary Human Hepatocytes

• Han KM
• Ahn SY
• Seo H
• Yun J
• Cha HJ
• Shin JS
• Kim YH
• Kim H
• Park HK
• Lee YM

• KMID: 2378807
• DOI: http://doi.org/10.4062/biomolther.2016.153

Abstract

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.

Keyword

Drug-drug interaction; CYP450; OATP transporters; Rifampin; Bosentan

MeSH Terms

Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System*
Cytochromes*
Gene Expression
HEK293 Cells
Hepatocytes*
Humans*
In Vitro Techniques
Incidence
Organic Anion Transporters
Polypharmacy
Rifampin*
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System
Cytochromes
Organic Anion Transporters
Rifampin