2017
DOI: 10.1080/00498254.2017.1393582
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Substrate-dependent effects of molecular-targeted anticancer agents on activity of organic anion transporting polypeptide 1B1

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), … Show more

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Cited by 13 publications
(10 citation statements)
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“…Notably, the organic-anion-transporting polypeptide (OATP) family ( SLCO genes) may be involved in the transport of TKIs used against HCC. OATP1B1 and OATP1B3 can mediate the uptake of cabozantinib [ 12 ], while OATP1B1 can also transport regorafenib [ 13 ] and probably lenvatinib [ 14 ]. However, there is a controversy regarding OATP-mediated sorafenib transport.…”
Section: Drug Uptake and Export (Moc-1)mentioning
confidence: 99%
“…Notably, the organic-anion-transporting polypeptide (OATP) family ( SLCO genes) may be involved in the transport of TKIs used against HCC. OATP1B1 and OATP1B3 can mediate the uptake of cabozantinib [ 12 ], while OATP1B1 can also transport regorafenib [ 13 ] and probably lenvatinib [ 14 ]. However, there is a controversy regarding OATP-mediated sorafenib transport.…”
Section: Drug Uptake and Export (Moc-1)mentioning
confidence: 99%
“…The following are some of the elements that can potentially contribute to the reported inconsistencies: Inhibitor concentration: A large number of the published articles have relied on the use of a single concentration of TKI, although regulatory guidance documents specifically recommend the need to perform experiments with at least 3–4 different concentrations, in order to more rigorously evaluate potential inhibitory properties. This is exemplified by a recent study involving the TKIs afatinib, nintedanib, lenvatinib, and ceritinib in which diverse degrees of inhibition were observed depending on the concentration (up to 30 µM), and where some concentrations would even increase transport function [ 66 ]. As TKIs tend to get concentrated in the liver and can potentially increase intracellular levels that are much higher than concurrent levels in plasma [ 2 ], the selection of relevant concentration ranges to be used in in vitro uptake studies requires careful consideration.…”
Section: Effects Of Tkis On the Function Of Oatp1b1 And Oatp1b3mentioning
confidence: 99%
“… Substrate selection: Since substrate-dependent inhibition by xenobiotics, including TKIs, has been well documented and is acknowledged expressly in the FDA guidance document, the degree to which findings obtained with one particular substrate can be extrapolated to other conditions is uncertain, and potentially accounts for several reported inconsistencies. Substrate-dependent inhibition has been previously reported when comparing inhibitory properties in OATP1B1-overexpressed models comparing the substrates fluorescein (FL), 2′,7′-dichlorofluorescein (DCF), atorvastatin, SN-38, and valsartan, as well as in a recent study comparing E2G and 8Fc-A [ 66 ], where some TKIs such as lapatinib, pazopanib, and nintedanib show inhibitory effects with some but not all test substrates. The difference between the results for different substrates is occasionally quite substantial; for example, ceritinib can cause 50% inhibition of OATP1B1 function when using FL, DCF, atorvastatin, or SN-38 as test substrates, but causes an apparent increase (by 50%) in OATP1B1-mediated transport of valsartan.…”
Section: Effects Of Tkis On the Function Of Oatp1b1 And Oatp1b3mentioning
confidence: 99%
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“…Several approaches are used to investigate and predict the complex issue of drug-induced transporter inhibition. The topic is widely described in in vitro assays, but the translational information to patients is questioned because the inhibition is mainly tested with prototypical and not clinically relevant substrates (Belzer et al, 2013;Martínez-Guerrero and Wright, 2013;Izumi et al, 2015;Pedersen et al, 2017;Koide et al, 2018). In the liver, several pharmacokinetic models describe how transporter inhibition modifies the drug clearances (CLs) across these transporters to explain and predict the modified systemic concentrations induced by inhibitors (Watanabe et al, 2010;Yoshida et al, 2012;Unadkat, 2016, 2018;Benet et al, 2018a,b).…”
Section: Introductionmentioning
confidence: 99%