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New Insights into Transporters in Drug Development

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biopharmaceutics".

Deadline for manuscript submissions: 10 November 2024 | Viewed by 3792

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Special Issue Editors

Dr. Sook Wah Yee

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Guest Editor

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
Interests: pharmacogenomics; membrane transporters; orphan transporter

Dr. Hong Shen

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Guest Editor

Department of Drug Metabolism and Pharmacokinetics (DMPK), Bristol Myers Squibb, Princeton, NJ, USA
Interests: transporter biomarkers; drug transporters; pharmacokinetics

Special Issue Information

Dear Colleagues,

You're invited to submit an article for a Special Issue on “New Insights into Transporters in Drug Development”. As a respected leader in this field, your expertise would make a valuable contribution to this Special Issue.

The Special Issue aims to highlight the recent advances in the research on transporters and their role in drug development. Original research articles, reviews, and perspectives are welcome on topics including, but not limited to, the following:

Endogenous biomarkers for drug transporters;
Transporter proteomics-based in vitro-to-in vivo extrapolation;
Physiologically-based pharmacokinetic models for predicting transporter-mediated drug interactions;
Computational and experimental approaches to identify transporter ligands, substrates, and inhibitors;
Resources and tools relevant to transporters in drug development;
Clinical implications of transporter-mediated drug disposition and response.

Your contribution to this important topic is eagerly anticipated.

Sincerely,

Dr. Sook Wah Yee
Dr. Hong Shen
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

membrane transporters
drug–drug interactions
in vitro-to-in vivo extrapolation
transporters as therapeutic targets
regulation of transporter expression and activity

Published Papers (4 papers)

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Research

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13 pages, 1303 KiB

Open AccessArticle

Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters

by Chetan P. Kulkarni, Jia Yang, Megan L. Koleske, Giovanni Lara, Khondoker Alam, Andre Raw, Bhagwant Rege, Liang Zhao, Dongmei Lu, Lei Zhang, Lawrence X. Yu, Robert A. Lionberger, Kathleen M. Giacomini, Deanna L. Kroetz and Sook Wah Yee

Pharmaceutics 2024, 16(5), 647; https://doi.org/10.3390/pharmaceutics16050647 - 10 May 2024

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Abstract

The presence of mutagenic and carcinogenic N-nitrosamine impurities in medicinal products poses a safety risk. While incorporating antioxidants in formulations is a potential mitigation strategy, concerns arise regarding their interference with drug absorption by inhibiting intestinal drug transporters. Our study screened thirty antioxidants for inhibitory effects on key intestinal transporters—OATP2B1, P-gp, and BCRP in HEK-293 cells (OATP2B1) or membrane vesicles (P-gp, BCRP) using ³H-estrone sulfate, ³H-N-methyl quinidine, and ³H-CCK8 as substrates, respectively. The screen identified that butylated hydroxyanisole (BHA) and carnosic acid inhibited all three transporters (OATP2B1, P-gp, and BCRP), while ascorbyl palmitate (AP) inhibited OATP2B1 by more than 50%. BHA had IC₅₀ values of 71 ± 20 µM, 206 ± 14 µM, and 182 ± 49 µM for OATP2B1, BCRP, and P-gp, respectively. AP exhibited IC₅₀ values of 23 ± 10 µM for OATP2B1. The potency of AP and BHA was tested with valsartan, an OATP2B1 substrate, and revealed IC₅₀ values of 26 ± 17 µM and 19 ± 11 µM, respectively, in HEK-293-OATP2B1 cells. Comparing IC₅₀ values of AP and BHA with estimated intestinal concentrations suggests an unlikely inhibition of intestinal transporters at clinical concentrations of drugs formulated with antioxidants. Full article

(This article belongs to the Special Issue New Insights into Transporters in Drug Development)

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16 pages, 3363 KiB

Open AccessArticle

Topotecan and Ginkgolic Acid Inhibit the Expression and Transport Activity of Human Organic Anion Transporter 3 by Suppressing SUMOylation of the Transporter

by Zhou Yu and Guofeng You

Pharmaceutics 2024, 16(5), 638; https://doi.org/10.3390/pharmaceutics16050638 - 9 May 2024

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Abstract

Organic anion transporter 3 (OAT3), expressed at the basolateral membrane of kidney proximal tubule cells, facilitates the elimination of numerous metabolites, environmental toxins, and clinically important drugs. An earlier investigation from our laboratory revealed that OAT3 expression and transport activity can be upregulated by SUMOylation, a post-translational modification that covalently conjugates SUMO molecules to substrate proteins. Topotecan is a semi-synthetic derivative of the herbal extract camptothecin, approved by the FDA to treat several types of cancer. Ginkgolic acid (GA) is one of the major components in the extract of Ginkgo biloba leaves that has long been used in food supplements for preventing dementia, high blood pressure, and supporting stroke recovery. Both topotecan and GA have been shown to affect protein SUMOylation. In the current study, we tested our hypothesis that topotecan and GA may regulate OAT3 SUMOylation, expression, and transport function. Our data show that the treatment of OAT3-expressing cells with topotecan or GA significantly decreases the SUMOylation of OAT3 by 50% and 75%, respectively. The same treatment also led to substantial reductions in OAT3 expression and the OAT3-mediated transport of estrone sulfate, a prototypical substrate. Such reductions in cell surface expression of OAT3 correlated well with an increased rate of OAT3 degradation. Mechanistically, we discovered that topotecan enhanced the association between OAT3 and the SUMO-specific protease SENP2, a deSUMOylation enzyme, which contributed to the significant decrease in OAT3 SUMOylation. In conclusion, this study unveiled a novel role of topotecan and GA in inhibiting OAT3 expression and transport activity and accelerating OAT3 degradation by suppressing OAT3 SUMOylation. During comorbidity therapies, the use of topotecan or Ginkgo biloba extract could potentially decrease the transport activity of OAT3 in the kidneys, which will in turn affect the therapeutic efficacy and toxicity of many other drugs that are substrates for the transporter. Full article

(This article belongs to the Special Issue New Insights into Transporters in Drug Development)

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Review

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16 pages, 937 KiB

Open AccessEditor’s ChoiceReview

Impact of Drug-Mediated Inhibition of Intestinal Transporters on Nutrient and Endogenous Substrate Disposition…an Afterthought?

by Kshitee Kharve, Andrew S. Engley, Mary F. Paine and Jason A. Sprowl

Pharmaceutics 2024, 16(4), 447; https://doi.org/10.3390/pharmaceutics16040447 - 24 Mar 2024

Viewed by 799

Abstract

A large percentage (~60%) of prescription drugs and new molecular entities are designed for oral delivery, which requires passage through a semi-impervious membrane bilayer in the gastrointestinal wall. Passage through this bilayer can be dependent on membrane transporters that regulate the absorption of nutrients or endogenous substrates. Several investigations have provided links between nutrient, endogenous substrate, or drug absorption and the activity of certain membrane transporters. This knowledge has been key in the development of new therapeutics that can alleviate various symptoms of select diseases, such as cholestasis and diabetes. Despite this progress, recent studies revealed potential clinical dangers of unintended altered nutrient or endogenous substrate disposition due to the drug-mediated disruption of intestinal transport activity. This review outlines reports of glucose, folate, thiamine, lactate, and bile acid (re)absorption changes and consequent adverse events as examples. Finally, the need to comprehensively expand research on intestinal transporter-mediated drug interactions to avoid the unwanted disruption of homeostasis and diminish therapeutic adverse events is highlighted. Full article

(This article belongs to the Special Issue New Insights into Transporters in Drug Development)

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17 pages, 1398 KiB

Open AccessReview

Multiple Regulatory Signals and Components in the Modulation of Bicarbonate Transporters

by Hyeong Jae Kim and Jeong Hee Hong

Pharmaceutics 2024, 16(1), 78; https://doi.org/10.3390/pharmaceutics16010078 - 5 Jan 2024

Viewed by 1227

Abstract

Bicarbonate transporters are responsible for the appropriate flux of bicarbonate across the plasma membrane to perform various fundamental cellular functions. The functions of bicarbonate transporters, including pH regulation, cell migration, and inflammation, are highlighted in various cellular systems, encompassing their participation in both physiological and pathological processes. In this review, we focused on recently identified modulatory signaling components that regulate the expression and activity of bicarbonate transporters. Moreover, we addressed recent advances in our understanding of cooperative systems of bicarbonate transporters and channelopathies. This current review aims to provide a new, in-depth understanding of numerous human diseases associated with the dysfunction of bicarbonate transporters. Full article

(This article belongs to the Special Issue New Insights into Transporters in Drug Development)

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