Biochemical interaction of anti-HCV telaprevir with the ABC transporters P-glycoprotein and breast cancer resistance protein

BMC Research Notes

Yoshikazu Sugimoto¹  Kazuhiro Katayama¹  Tomonori Suzuki¹  Kohji Noguchi¹  Yuria Fujita¹ 

[1] Division of Chemotherapy, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan

关键词: Photoaffinity labeling;    HCV;    [¹²⁵I]-IAAP;    Kinetics;    Vesicle transporter assay;    Transporter;    Inhibition;    Telaprevir;    Breast cancer resistance protein;    P-glycoprotein;   

Others  :  1140911
DOI  :  10.1186/1756-0500-6-445

 received in 2013-08-23, accepted in 2013-11-05,  发布年份 2013

【 摘 要 】

Background

The ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp)/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2 are involved in the intestinal absorption and renal excretion of various substrate drugs. Their activities affect sub-therapeutic drug concentrations and excretion of natural transporter substrates. The new oral anti-HCV drug telaprevir has dramatically improved the efficacy of hepatitis-C virus (HCV) treatment, and recent studies have suggested a possible pharmacological interaction between telaprevir and P-gp. We studied the kinetics of in vitro interactions between telaprevir and P-gp and BCRP to understand the molecular basis of that interaction.

Findings

The effect of telaprevir on P-gp- and BCRP-mediated transport was evaluated by an in vitro vesicle transporter assay using different transport substrates, and the kinetics of transporter inhibition was determined. The results showed that telaprevir could inhibit P-gp- and BCRP-mediated transport in the in vitro vesicle transport assay, with each IC₅₀ values of ≈ 7 μmol/L and ≈ 30 μmol/L, respectively. Analyses of Lineweaver–Burk plots showed that telaprevir was likely to be a competitive inhibitor against P-gp and BCRP. Photoaffinity labeling experiments were employed to observe competitive inhibition by telaprevir using iodoarylazidoprazosin (IAAP) as a binding substrate for P-gp and BCRP. These experiments revealed that telaprevir inhibited [¹²⁵I]-IAAP-binding with P-gp and BCRP.

Conclusion

Telaprevir competitively inhibited P-gp and BCRP, and P-gp-mediated transport was more sensitive to telaprevir compared with BCRP-mediated transport. These data suggest that telaprevir represses the transporter functions of P-gp and BCRP via direct inhibition.

【 授权许可】

   
2013 Fujita et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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