Bosentan and Rifampin Interactions Modulate Influx Transporter and Cytochrome P450 Expression and Activities in Primary Human Hepatocytes.
10.4062/biomolther.2016.153
- Author:
Kyoung Moon HAN
1
;
Sun Young AHN
;
Hyewon SEO
;
Jaesuk YUN
;
Hye Jin CHA
;
Ji Soon SHIN
;
Young Hoon KIM
;
Hyungsoo KIM
;
Hye kyung PARK
;
Yong Moon LEE
Author Information
1. Pharmacological Research Division, Toxicological and Research Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju 28159, Republic of Korea. lovelyhkm@korea.kr
- Publication Type:Original Article
- Keywords:
Drug-drug interaction;
CYP450;
OATP transporters;
Rifampin;
Bosentan
- MeSH:
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*
- From:Biomolecules & Therapeutics
2017;25(3):288-295
- CountryRepublic of Korea
- Language:English
-
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.
