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), 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.

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

“…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.…”

Role of OATP1B1 and OATP1B3 in Drug-Drug Interactions Mediated by Tyrosine Kinase Inhibitors

“…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.…”

“… 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.…”

“…While this is a generally useful approach, several published examples highlight the limitations associated with this strategy. For example, Koide et al, have demonstrated that the use of DCF as a model substrate generates the lowest IC 50 values for most but not necessarily all substrate-inhibitor combinations [ 66 , 68 ] and that TKIs with known OATP1B1-inhibitory properties, such as pazopanib, fail to affect transport function when using the clinically relevant substrates atorvastatin and valsartan [ 70 , 71 , 72 , 73 ]. The reported differences in inhibitory properties of TKIs toward the function of transporters such as OATP1B1 as a function of the test substrate used in in vitro studies can directly impact calculated R-values, and influence the reliability of DDI predictions and the clinical decision-making process, especially for weak-to-moderate inhibitors [ 74 ].…”

Hepatocyte Concentrations of Imaging Compounds Associated with Transporter Inhibition: Evidence in Perfused Rat Livers

“…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).…”