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Contribution of Membrane Transporters to the Disposition of Organic Cations

Uddin, Muhammad Erfan
http://orcid.org/0000-0002-7160-0455
http://rave.ohiolink.edu/etdc/view?acc_num=osu1648139112543107

Abstract Details

2022, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Membrane transporters play a pivotal role in maintaining cellular integrity via the removal of toxic metabolites or entry of essential nutrients. Despite regulating cellular influx and efflux, tissue-specific expression of transporters contributes to local drug accumulation and drug-drug interactions (DDIs), and functional alterations in these transporters can directly influence an individual’s susceptibility to drug-induced toxicity. Here, we provide an overview of membrane transporters with a role in drug-induced toxicity and discuss novel strategies to improve therapeutic outcomes. We highlighted the contribution of membrane transporters in chemotherapy-induced various toxicities (Chapter 1). We then evaluated in vitro and in vivo functional regulation of organic cation transporter 1 (OCT1), a most abundant cationic transporter expressed in the liver, and identified an OCT1 specific biomarker isobutyryl L-carnitine (IBC) in plasma (Chapter 2). Next, we evaluated the interactions with FDA-approved tyrosine kinase inhibitors (TKIs) with MATE1 transporter, which is highly expressed in the apical membrane of renal tubular cells, and evaluated the effect of MATE1 inhibition on the safety or DDI liability of oxaliplatin-based chemotherapy (Chapter 3). Finally, we characterized the transport mechanism of dofetilide, a class III anti-arrhythmic drug. We investigated the in vitro, ex vivo, and in vivo DDI potential of dofetilide, and the influence of MATE1 transporter on dofetilide disposition. In addition, we developed a physiologically-based pharmacokinetic (PBPK) model to predict transporter-mediated DDIs (Chapter 4).
Alex Sparreboom (Advisor)
Navjot Pabla (Committee Member)
Cynthia Carnes (Committee Member)
Shuiying Hu (Advisor)
233 p.
Pharmacology; Pharmacy Sciences
Membrane Transporters, OCT1, MATE1, Dofetilide, PBPK Modeling

Recommended Citations

Citations

  • Uddin, M. E. (2022). Contribution of Membrane Transporters to the Disposition of Organic Cations [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1648139112543107

    APA Style (7th edition)

  • Uddin, Muhammad Erfan. Contribution of Membrane Transporters to the Disposition of Organic Cations. 2022. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1648139112543107.

    MLA Style (8th edition)

  • Uddin, Muhammad Erfan. "Contribution of Membrane Transporters to the Disposition of Organic Cations." Doctoral dissertation, Ohio State University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=osu1648139112543107

    Chicago Manual of Style (17th edition)

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