Alisertib shows negligible potential for perpetrating pharmacokinetic drug-drug interactions on ABCB1, ABCG2 and cytochromes P450, but acts as dual-activity resistance modulator through the inhibition of ABCC1 transporter

Vagiannis, Dimitrios; Budagaga, Youssif; Novotná, Eva; Skarka, Adam; Kammerer, Sarah; Küpper, Jan-Heiner; Hofman, Jakub

doi:10.1016/j.taap.2021.115823

Cited by 11 publications

(6 citation statements)

References 55 publications

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“…These results are supported by the previous report that suggests alisertib is a P-gp substrate, not only by comparing accumulation of alisertib in Caco-2 cells in presence and absence of verapamil, but also by showing higher brain uptake of [ 11 C]-alisertib in P-gp knockout mice compared to wild-type mice (Goos et al, 2016). Recently, it was demonstrated that alisertib was transported by ABCB1 by the bidirectional study in a MDCKII-ABCB1 transfected cell line (Vagiannis et al, 2022).…”

Section: Discussionsupporting

confidence: 88%

Murine Central Nervous System and Bone Marrow Distribution of the Aurora A Kinase Inhibitor Alisertib: Pharmacokinetics and Exposure at the Sites of Efficacy and Toxicity

Power

Zhang

et al. 2022

J Pharmacol Exp Ther

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Important challenges in developing drugs that target central nervous system (CNS) tumors include overcoming barriers for CNS delivery and reducing systemic side effects. Alisertib, an aurora A kinase inhibitor, has been examined for treatment of several CNS tumors in preclinical and clinical studies. In this study, we investigated the distribution of alisertib into the CNS, the site of efficacy for brain tumors, and into the bone marrow, the site of dose-limiting toxicity leading to myelosuppression. Mechanisms influencing site-specific distribution, such as active transport mediated by the efflux proteins, pglycoprotein (P-gp) and breast cancer resistance protein (Bcrp), were examined. Alisertib exposure to the brain in wild-type mice was less than 1% of that in the plasma, and was evenly distributed throughout various brain regions and the spinal cord. Studies using transporter knockout mice and pharmacological inhibition show that alisertib CNS distribution is influenced by P-gp, but not Bcrp. Conversely, upon systemic administration, alisertib distribution to the bone marrow occurred rapidly, was not significantly limited by efflux transporters, and reached higher concentrations than in the CNS. This study demonstrates that, given an equivalent distributional driving force exposure in plasma, the exposure of alisertib in the brain is significantly less than that in the bone marrow, suggesting that targeted delivery may be necessary to guarantee therapeutic efficacy with minimal risk for adverse events. Therefore, these data suggest that, to improve the therapeutic index when using alisertib for brain tumors, a localized regional delivery, such as convection-enhanced delivery, may be warranted.

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Section: Discussionsupporting

confidence: 88%

Murine Central Nervous System and Bone Marrow Distribution of the Aurora A Kinase Inhibitor Alisertib: Pharmacokinetics and Exposure at the Sites of Efficacy and Toxicity

Power

Zhang

et al. 2022

J Pharmacol Exp Ther

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“…In general, highly hydrophilic drugs are more susceptible to drug resistance than highly lipophilic agents due to the overwhelming effect of passive diffusion over the membrane carrier-mediated transport in the latter case [41]. We have previously shown that the time-dependent reaching of concentration equilibrium can result in conflicting outcomes of experiments with short vs. long incubation periods [22]. As encorafenib is commonly administered once daily for a total interval of more than 20 weeks [42], it is likely that our proliferation studies are more relevant concerning the prediction of resistance victim properties than the above-discussed brain penetration studies.…”

Section: Discussionmentioning

confidence: 99%

“…The drug accumulation study was performed following the descriptions in our previous papers [20][21][22]. MDCKII-par, MDCKII-ABCB1, MDCKII-ABCG2, MDCKII-ABCC1, and lung cancer explant cultures were seeded in 12-well plates at the densities of 2.2 × 10 5 , 1.5 × 10 5 , 2.5 × 10 5 , 2.2 × 10 5 , 1.5 × 10 5 cells/well, respectively.…”

Section: Drug Accumulation Study For Abc Transportersmentioning

confidence: 99%

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Encorafenib Acts as a Dual-Activity Chemosensitizer through Its Inhibitory Effect on ABCC1 Transporter In Vitro and Ex Vivo

et al. 2022

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Encorafenib (LGX818, trade name Braftovi), a novel BRAF inhibitor, has been approved for the treatment of melanoma and colorectal cancer. In the present work, we evaluated encorafenib’s possible antagonistic effects on the pharmacokinetic mechanisms of multidrug resistance (MDR), as well as its perpetrator role in drug interactions. Firstly, encorafenib potently inhibited the efflux function of the ABCC1 transporter in drug accumulation assays, while moderate and null interaction levels were recorded for ABCB1 and ABCG2, respectively. In contrast, the mRNA expression levels of all the tested transporters were not altered by encorafenib. In the drug combination studies, we found that daunorubicin and topotecan resistances were synergistically attenuated by the encorafenib-mediated interaction in A431-ABCC1 cells. Notably, further experiments in ex vivo patient-derived explants confirmed the MDR-modulating ability of encorafenib. Advantageously, the overexpression of tested drug efflux transporters failed to hinder the antiproliferative activity of encorafenib. In addition, no significant modulation of the CYP3A4 enzyme’s activity by encorafenib was observed. In conclusion, our work indicated that encorafenib can act as an effective chemosensitizer targeting the ABCC1-induced MDR. Our in vitro and ex vivo data might provide valuable information for designing the novel effective scheme applicable in the clinical pharmacotherapy of BRAF-mutated/ABCC1-expressing tumors.

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“…New reports particularly from 2021 and 2022 were taken into consideration to update the dataset with compounds that were evaluated against the three transporters ABCB1, ABCC1, and ABCG2. In total, 22 new compounds were included into the list of qualified compounds 7 , 40 – 42 . In addition, we focused an extended literature search, particularly of known standard inhibitors of ABCB1, ABCC1, and ABCG2 to obtain bioactivities with less mathematical uncertainty which also align well with our empirical experience in the laboratory.…”

Section: Methodsmentioning

confidence: 99%

A curated binary pattern multitarget dataset of focused ATP-binding cassette transporter inhibitors

et al. 2022

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Multitarget datasets that correlate bioactivity landscapes of small-molecules toward different related or unrelated pharmacological targets are crucial for novel drug design and discovery. ATP-binding cassette (ABC) transporters are critical membrane-bound transport proteins that impact drug and metabolite distribution in human disease as well as disease diagnosis and therapy. Molecular-structural patterns are of the highest importance for the drug discovery process as demonstrated by the novel drug discovery tool ‘computer-aided pattern analysis’ (‘C@PA’). Here, we report a multitarget dataset of 1,167 ABC transporter inhibitors analyzed for 604 molecular substructures in a statistical binary pattern distribution scheme. This binary pattern multitarget dataset (ABC_BPMDS) can be utilized for various areas. These areas include the intended design of (i) polypharmacological agents, (ii) highly potent and selective ABC transporter-targeting agents, but also (iii) agents that avoid clearance by the focused ABC transporters [e.g., at the blood-brain barrier (BBB)]. The information provided will not only facilitate novel drug prediction and discovery of ABC transporter-targeting agents, but also drug design in general in terms of pharmacokinetics and pharmacodynamics.

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Alisertib shows negligible potential for perpetrating pharmacokinetic drug-drug interactions on ABCB1, ABCG2 and cytochromes P450, but acts as dual-activity resistance modulator through the inhibition of ABCC1 transporter

Cited by 11 publications

References 55 publications

Murine Central Nervous System and Bone Marrow Distribution of the Aurora A Kinase Inhibitor Alisertib: Pharmacokinetics and Exposure at the Sites of Efficacy and Toxicity

Murine Central Nervous System and Bone Marrow Distribution of the Aurora A Kinase Inhibitor Alisertib: Pharmacokinetics and Exposure at the Sites of Efficacy and Toxicity

Encorafenib Acts as a Dual-Activity Chemosensitizer through Its Inhibitory Effect on ABCC1 Transporter In Vitro and Ex Vivo

A curated binary pattern multitarget dataset of focused ATP-binding cassette transporter inhibitors

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