Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors
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Varun Khurana
Abstract
Background: The potential of tyrosine kinase inhibitors (TKIs) interacting with other therapeutics through hepatic uptake transporter inhibition has not been fully delineated in drug-drug interactions (DDIs). This study was designed to estimate the half-maximal inhibitory concentration (IC50) values of five small-molecule TKIs (pazopanib, nilotinib, vandetanib, canertinib and erlotinib) interacting with organic anion-transporting polypeptides (OATPs): OATP-1B1 and -1B3.
Methods: The IC50 values of TKIs and rifampicin (positive control) were determined by concentration-dependent inhibition of TKIs on cellular accumulation of radiolabeled probe substrates [3H]estrone sulfate and [3H]cholecystokinin octapeptide. Chinese hamster ovary cells transfected with humanized OATP-1B1 and OATP-1B3 transporter proteins, respectively, were utilized to carry out these studies.
Results: Pazopanib and nilotinib show inhibitory activity on OATP-1B1 transporter protein. IC50 values for rifampicin, pazopanib and nilotinib were 10.46±1.15, 3.89±1.21 and 2.78±1.13 μM, respectively, for OATP-1B1 transporter. Vandetanib, canertinib and erlotinib did not exhibit any inhibitory potency toward OATP-1B1 transporter protein. Only vandetanib expressed inhibitory potential toward OATP-1B3 transporter protein out of the five selected TKIs. IC50 values for rifampicin and vandetanib for OATP-1B3 transporter inhibition were 3.67±1.20 and 18.13±1.21 μM, respectively. No significant inhibition in the presence of increasing concentrations of pazopanib, nilotinib, canertinib and erlotinib were observed for OATP-1B3 transporter.
Conclusions: Because selected TKIs are inhibitors of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter-mediated DDIs. These findings provide the basis for further preclinical and clinical studies investigating the transporter-based DDI potential of TKIs.
Acknowledgments
This work was supported by National Institutes of Health grant 1R01 AI071199. The authors highly appreciate Dr. Bruno Stieger for the generous gift of OATP-1B-type transporter protein transfected cell lines.
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
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©2014 by De Gruyter
Artikel in diesem Heft
- Frontmatter
- Editorial
- CYP 2C19 and UDP-glucuronosyltransferases not only for drugs but also for endobiotics
- Review
- Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy
- Reviews in Population Pharmacogenomics
- Pharmacogenetics in Jewish populations
- Frequency of CYP450 enzyme gene polymorphisms in the Greek population: review of the literature, original findings and clinical significance
- Original Articles
- Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors
- Effect of silymarin pretreatment on the bioavailability of domperidone in healthy human volunteers
- In vitro inhibitory effects of herbal supplements on tamoxifen and irinotecan metabolism
- Acknowledgment
- Acknowledgment
Artikel in diesem Heft
- Frontmatter
- Editorial
- CYP 2C19 and UDP-glucuronosyltransferases not only for drugs but also for endobiotics
- Review
- Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy
- Reviews in Population Pharmacogenomics
- Pharmacogenetics in Jewish populations
- Frequency of CYP450 enzyme gene polymorphisms in the Greek population: review of the literature, original findings and clinical significance
- Original Articles
- Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors
- Effect of silymarin pretreatment on the bioavailability of domperidone in healthy human volunteers
- In vitro inhibitory effects of herbal supplements on tamoxifen and irinotecan metabolism
- Acknowledgment
- Acknowledgment
