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Interactions between multi-kinase inhibitors and solute carrier transporters

Chen, Mingqing
http://rave.ohiolink.edu/etdc/view?acc_num=osu1585741410361704

Abstract Details

2020, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Tyrosine kinase inhibitors (TKIs) represent the largest class of anti-cancer drugs. By the end of 2019, there are a total of 46 granted FDA approval for different indications, and more are currently in various stages of development. TKIs were designed to specifically target tyrosine kinases that are involved in cancer development, including tumor cell proliferation and growth, apoptosis, and promotion of angiogenesis and metastasis. As targeted chemotherapy, TKIs are designed to target specific mutated kinase or kinases involved in particular subtypes of the tumor and, thus, are expected to have a quicker response and are better tolerated. However, TKIs have their issues in the clinic. One of the significant limitations is exposure-related toxicities. Almost all TKIs have shown relatively large body surface area-irrelevant interpatient pharmacokinetic (PK) variability. Although all TKIs are cytochrome P450 3A4 (CYP3A4) substrates, the expression and function of CYP3A4 do not strongly correlate to TKI exposure for specific multi-kinase inhibitors (MKIs) like sorafenib and regorafenib. There must be other covariates that contribute to this variability. Another main concern is their interactions with crucial transporters in drug absorption, disposition, metabolism, and excretion (ADME). Cancer patients on TKIs are very likely to be on other commonly used medications like statins, which are well-accepted as substrates of hepatic organic anion transporting polypeptides (OATPs) and metformin which is a substrate of renal organic cation transporter (OCT)2 and multi-antimicrobial extrusion protein (MATE)1/2-K or other antitumor medications of which excretion is mainly mediated by transporters. The undesired TKI-transporter interactions, mostly inhibition, could eventually lead to increased systemic exposure of victim drugs and affect their local exposure and toxicity profile. In this study, we aimed to look at i) transporters involved in the disposition pathway of sorafenib (OCT1, OATP2B1) and regorafenib (OATP1B-type of transporters) in a variety of in vitro model systems and validated with transgenic transporter knockout mouse models; ii) underline mechanism for TKIs-OATP interactions with high throughput siKinase screen and validated in vitro with protein phosphorylation and in vivo. In the meanwhile, the involvement of OATP2B1 in oral drug absorption has been proposed for a decade with limited evidence. Lack of proper in-vivo model has limited our knowledge on this emerging transporter of clinical relevance. We generated a novel transgenic Oatp2b1 knockout mouse model to thoroughly study the involvement of this transporter in both intestinal and liver uptake of its probe substrate, fluvastatin. We also evaluated its vulnerary to TKI-related drug-drug interactions (DDIs). We found out that neither OCT1 nor OATP2B1 influence hepatic uptake of sorafenib both in vitro and in transporter-deficient mice and tumoral sorafenib was independent to OCT1 expression. The hepatic transporter facilitates its liver uptake remains unknown. Like what we have shown for sorafenib, regorafenib, whose structure is almost identical to sorafenib, except the fluorine atom in the central phenyl ring, did not get into the liver through OATP1B-type of transporters but its major metabolite, regorafenib-glucuronide (RG), relied on this transporter for biliary excretion. We also noticed a gender difference in Cyp3c11 expression in mice that lead to gender discrepancy in regorafenib-glucuronide exposure. We successfully generated a novel whole-genome Oatp2b1-knockout mouse model and validated the gene depletion at both gene and phenotypical level. The involvement of this transporter in drug absorption was confirmed with fluvastatin and the vulnerary to drug-drug interactions was confirmed with erlotinib, a TKI that has been shown as an OATP2B1 substrate/inhibitor. LYN kinase was identified as a leading candidate that regulates OATP1B1 function. Validation of OATP1B1 phosphorylation and effect of Lyn kinase knockdown in vivo is still ongoing.
Alex Sparreboom (Advisor)
Sharyn Baker (Committee Member)
Christopher Coss (Committee Member)
Kari Hoyt (Committee Member)
227 p.
Pharmaceuticals
drug transporter; DMPK; pharmacokinetics; drug-drug interactions

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Citations

  • Chen, M. (2020). Interactions between multi-kinase inhibitors and solute carrier transporters [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1585741410361704

    APA Style (7th edition)

  • Chen, Mingqing . Interactions between multi-kinase inhibitors and solute carrier transporters. 2020. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1585741410361704.

    MLA Style (8th edition)

  • Chen, Mingqing . "Interactions between multi-kinase inhibitors and solute carrier transporters." Doctoral dissertation, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1585741410361704

    Chicago Manual of Style (17th edition)

osu1585741410361704
374
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This open access ETD is published by The Ohio State University and OhioLINK.