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Substrate-dependent effects of molecular-targeted anticancer agents on activity of organic anion transporting
Hiroyoshi Koide1, Masayuki Tsujimoto1, Ai Takeuchi1
1a Department of Clinical Pharmacy , Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University , Kyoto , Japan.
Abstract:
1. Organic anion-transporting polypeptide 1B1 (OATP1B1) plays an important role in the hepatic uptake of a broad range of substrate drugs. In vitro experiments show that molecular-targeted agents do not always have similar effects on OATP1B1 activity. 2. The purpose of this study was to clarify whether the effects of molecular-targeted agents on OATP1B1 are substrate-dependent. We used OATP1B1-transfected cells to compare the effects of molecular-targeted agents on OATP1B1-mediated uptake of fluorescein (FL), 2',7'-dichlorofluorescein (DCF), atorvastatin, SN-38 and valsartan. 3. Cabozantinib, cediranib, neratinib, pazopanib, regorafenib, sorafenib and tivantinib did not affect or only slightly affected OATP1B1-mediated substrate uptake. Nilotinib and lenvatinib moderately and strongly inhibited OATP1B1-mediated substrate uptake, respectively. In contrast, afatinib stimulated OATP1B1-mediated uptake of FL and SN-38, ceritinib stimulated that of valsartan, and nintedanib stimulated that of FL and valsartan. In addition, the effects of afatinib, ceritinib and nintedanib on OATP1B1 activity differed markedly depending on the type of substrate. Afatinib, ceritinib and nintedanib had a substrate-dependent effect on OATP1B1 activity. 4. We conclude that the evaluation of OATP1B1 activity using only a single probe substrate for some molecular-targeted agents may lead to a faulty understanding of their mechanisms of drug interactions.
Insights
Molecular-targeted agents can have varying effects on Organic Anion-Transporting Polypeptide 1B1 (OATP1B1) activity. This study found that drug interactions with OATP1B1 are substrate-dependent, impacting drug metabolism and efficacy.
Area of Science:
- Pharmacology
- Drug Metabolism
- Molecular Biology
Background:
- Organic anion-transporting polypeptide 1B1 (OATP1B1) is crucial for the liver's uptake of many drugs.
- Previous in vitro studies indicated that molecular-targeted agents do not consistently affect OATP1B1 activity.
Purpose of the Study:
- To investigate whether the impact of molecular-targeted agents on OATP1B1 is dependent on the specific substrate.
- To compare the effects of various molecular-targeted agents on OATP1B1-mediated uptake of different substrates.
Main Methods:
- Utilized OATP1B1-transfected cells to assess drug uptake.
- Compared the effects of several molecular-targeted agents on the OATP1B1-mediated transport of fluorescein (FL), 2',7'-dichlorofluorescein (DCF), atorvastatin, SN-38, and valsartan.
Main Results:
- Most tested agents showed minimal impact on OATP1B1 activity.
- Nilotinib and lenvatinib demonstrated moderate and strong inhibition, respectively.
- Afatinib, ceritinib, and nintedanib exhibited substrate-dependent stimulation of OATP1B1, with effects varying by substrate type.
Conclusions:
- The effects of certain molecular-targeted agents on OATP1B1 activity are substrate-dependent.
- Using a single probe substrate to evaluate OATP1B1 activity with these agents may lead to inaccurate conclusions about drug interaction mechanisms.