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Pharmaceutics
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New Insights into Transporters in Drug Development
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New Insights into Transporters in Drug Development

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

Deadline for manuscript submissions: closed (10 November 2024) | Viewed by 18435

Special Issue Editors

Dr. Sook Wah Yee

E-Mail Website
Guest Editor
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
Interests: pharmacogenomics; membrane transporters; orphan transporter
Dr. Hong Shen

E-Mail Website
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

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Published Papers (10 papers)

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Research

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14 pages, 1537 KiB  
Article
Effects of Sex and Cross-Sex Hormone Treatment on Renal MCT/SMCT Expression Following Prepubertal Gonadectomy
by Annie Lee, Qing Zhang, Hao Wei and Melanie A. Felmlee
Pharmaceutics 2025, 17(2), 252; https://doi.org/10.3390/pharmaceutics17020252 - 14 Feb 2025
Viewed by 488
Abstract
Background: Kidney proton- and sodium-dependent monocarboxylate transporters (MCT/SMCT) are involved in the renal reabsorption of substrates, and thus factors involved in their regulation may have pharmacokinetic implications. Previous studies have demonstrated sex hormone-dependent regulation of MCTs and SMCTs in tissues involved in drug [...] Read more.
Background: Kidney proton- and sodium-dependent monocarboxylate transporters (MCT/SMCT) are involved in the renal reabsorption of substrates, and thus factors involved in their regulation may have pharmacokinetic implications. Previous studies have demonstrated sex hormone-dependent regulation of MCTs and SMCTs in tissues involved in drug disposition. The present study evaluates the impact of puberty on renal MCT/SMCT expression with ovariectomy and castration conducted before puberty, removing the initial exposure to sex hormones. Methods: Male and female rats were castrated or ovariectomized before puberty (4 weeks of age), and subsequently treated with testosterone, 17β-estradiol, progesterone, or both 17β-estradiol and progesterone for 21 days starting at 10 weeks of age. MCT1, CD147, and SMCT1 membrane-bound kidney expression were quantified by Western blot. Results: SMCT1 and CD147 expression were significantly higher in OVX and CST rats treated with testosterone, and testosterone plasma concentrations showed a significant positive correlation with MCT1, SMCT1, and CD147 expression. CD147 expression was significantly downregulated in OVX rats treated with estrogen, compared to placebo controls, and estrogen plasma concentrations were significantly negatively correlated with CD147 expression. Conclusions: Sex and cross-sex hormone treatment altered MCT1, CD147, and SMCT1 expression when gonadectomy was conducted before puberty. The magnitude and direction of the expression differences differed when compared to animals that underwent gonadectomy after puberty, suggesting that sex hormone exposure during puberty plays a key role in MCT1/SMCT1 renal expression. Further studies are needed to elucidate the underlying mechanisms for the differential regulation of MCTs/SMCTs when gonadectomy occurs before or after puberty. Full article
(This article belongs to the Special Issue New Insights into Transporters in Drug Development)
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11 pages, 944 KiB  
Article
Altered Expression of BCRP Impacts Fetal Accumulation of Rosuvastatin in a Rat Model of Preeclampsia
by Wanying Dai and Micheline Piquette-Miller
Pharmaceutics 2024, 16(7), 884; https://doi.org/10.3390/pharmaceutics16070884 - 30 Jun 2024
Viewed by 1580
Abstract
Expression of the breast cancer resistance protein (BCRP/ABCG2) transporter is downregulated in placentas from women with preeclampsia (PE) and in an immunological rat model of PE. While many drugs are substrates of this important efflux transporter, the impact of PE associated BCRP downregulation [...] Read more.
Expression of the breast cancer resistance protein (BCRP/ABCG2) transporter is downregulated in placentas from women with preeclampsia (PE) and in an immunological rat model of PE. While many drugs are substrates of this important efflux transporter, the impact of PE associated BCRP downregulation on maternal and fetal drug exposure has not been investigated. Using the PE rat model, we performed a pharmacokinetic study with rosuvastatin (RSV), a BCRP substrate, to investigate this impact. PE was induced in rats during gestational days (GD) 13 to 16 with daily low-dose endotoxin. On GD18, RSV (3 mg/kg) was administrated intravenously, and rats were sacrificed at time intervals between 0.5 and 6 h. As compared to controls, placental expression of Bcrp and Oatp2b1 significantly decreased in PE rats. A corresponding increase in RSV levels was seen in fetal tissues and amniotic fluid of the PE group (p < 0.05), while maternal plasma concentrations remained unchanged from the controls. An increase in Bcrp expression and decreased RSV concentration were seen in the livers of PE dams. This suggests that PE-mediated transporter dysregulation leads to significant changes in the maternal and fetal RSV disposition. Overall, our findings demonstrate that altered placental expression of transporters in PE can increase fetal accumulation of their substrates. Full article
(This article belongs to the Special Issue New Insights into Transporters in Drug Development)
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11 pages, 220 KiB  
Communication
Expanding Role of Endogenous Biomarkers for Assessment of Transporter Activity in Drug Development: Current Applications and Future Horizon
by Vikram Arya, Joseph D. Ma and Kine Eide Kvitne
Pharmaceutics 2024, 16(7), 855; https://doi.org/10.3390/pharmaceutics16070855 - 25 Jun 2024
Cited by 3 | Viewed by 1898
Abstract
The evaluation of transporter-mediated drug–drug interactions (DDIs) during drug development and post-approval contributes to benefit–risk assessment and helps formulate clinical management strategies. The use of endogenous biomarkers, which are substrates of clinically relevant uptake and efflux transporters, to assess the transporter inhibitory potential [...] Read more.
The evaluation of transporter-mediated drug–drug interactions (DDIs) during drug development and post-approval contributes to benefit–risk assessment and helps formulate clinical management strategies. The use of endogenous biomarkers, which are substrates of clinically relevant uptake and efflux transporters, to assess the transporter inhibitory potential of a drug has received widespread attention. Endogenous biomarkers, such as coproporphyrin (CP) I and III, have increased mechanistic understanding of complex DDIs. Other endogenous biomarkers are under evaluation, including, but not limited to, sulfated bile acids and 4-pyridoxic acid (PDA). The role of endogenous biomarkers has expanded beyond facilitating assessment of transporter-mediated DDIs and they have also been used to understand alterations in transporter activity in the setting of organ dysfunction and various disease states. We envision that endogenous biomarker-informed approaches will not only help to formulate a prudent and informed DDI assessment strategy but also facilitate quantitative predictions of changes in drug exposures in specific populations. Full article
(This article belongs to the Special Issue New Insights into Transporters in Drug Development)
21 pages, 5620 KiB  
Article
Study on the Effect of Pharmaceutical Excipient PEG400 on the Pharmacokinetics of Baicalin in Cells Based on MRP2, MRP3, and BCRP Efflux Transporters
by Dan Yang, Min Zhang, Mei Zhao, Chaoji Li, Leyuan Shang, Shuo Zhang, Pengjiao Wang and Xiuli Gao
Pharmaceutics 2024, 16(6), 731; https://doi.org/10.3390/pharmaceutics16060731 - 29 May 2024
Cited by 3 | Viewed by 1460
Abstract
Pharmaceutical excipient PEG400 is a common component of traditional Chinese medicine compound preparations. Studies have demonstrated that pharmaceutical excipients can directly or indirectly influence the disposition process of active drugs in vivo, thereby affecting the bioavailability of drugs. In order to reveal the [...] Read more.
Pharmaceutical excipient PEG400 is a common component of traditional Chinese medicine compound preparations. Studies have demonstrated that pharmaceutical excipients can directly or indirectly influence the disposition process of active drugs in vivo, thereby affecting the bioavailability of drugs. In order to reveal the pharmacokinetic effect of PEG400 on baicalin in hepatocytes and its mechanism, the present study first started with the effect of PEG400 on the metabolic disposition of baicalin at the hepatocyte level, and then the effect of PEG400 on the protein expression of baicalin-related transporters (BCRP, MRP2, and MRP3) was investigated by using western blot; the effect of MDCKII-BCRP, MDCKII-BCRP, MRP2, and MRP3 was investigated by using MDCKII-BCRP, MDCKII-MRP2, and MDCKII-MRP3 cell monolayer models, and membrane vesicles overexpressing specific transporter proteins (BCRP, MRP2, and MRP3), combined with the exocytosis of transporter-specific inhibitors, were used to study the effects of PEG400 on the transporters in order to explore the possible mechanisms of its action. The results demonstrated that PEG400 significantly influenced the concentration of baicalin in hepatocytes, and the AUC0–t of baicalin increased from 75.96 ± 2.57 μg·h/mL to 106.94 ± 2.22 μg·h/mL, 111.97 ± 3.98 μg·h/mL, and 130.42 ± 5.26 μg·h/mL (p ˂ 0.05). Furthermore, the efflux rate of baicalin was significantly reduced in the vesicular transport assay and the MDCKII cell model transport assay, which indicated that PEG400 had a significant inhibitory effect on the corresponding transporters. In conclusion, PEG400 can improve the bioavailability of baicalin to some extent by affecting the efflux transporters and thus the metabolic disposition of baicalin in the liver. Full article
(This article belongs to the Special Issue New Insights into Transporters in Drug Development)
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13 pages, 1303 KiB  
Article
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
Cited by 2 | Viewed by 2781
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 [...] Read more.
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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Graphical abstract

16 pages, 3363 KiB  
Article
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
Cited by 1 | Viewed by 1682
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 [...] Read more.
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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20 pages, 393 KiB  
Review
Nucleoside Reverse Transcriptase Inhibitor (NRTI)-Induced Neuropathy and Mitochondrial Toxicity: Limitations of the Poly-γ Hypothesis and the Potential Roles of Autophagy and Drug Transport
by John Haynes, Arnav Joshi, Ross C. Larue, Eric D. Eisenmann and Rajgopal Govindarajan
Pharmaceutics 2024, 16(12), 1592; https://doi.org/10.3390/pharmaceutics16121592 - 13 Dec 2024
Viewed by 1356
Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of highly active antiretroviral therapy (HAART)—the current standard of care for treating human immunodeficiency virus (HIV) infection. Despite their efficacy, NRTIs cause numerous treatment-limiting adverse effects, including a distinct peripheral neuropathy, called antiretroviral toxic neuropathy [...] Read more.
Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of highly active antiretroviral therapy (HAART)—the current standard of care for treating human immunodeficiency virus (HIV) infection. Despite their efficacy, NRTIs cause numerous treatment-limiting adverse effects, including a distinct peripheral neuropathy, called antiretroviral toxic neuropathy (ATN). ATN primarily affects the extremities with shock-like tingling pain, a pins-and-needles prickling sensation, and numbness. Despite its negative impact on patient quality of life, ATN remains poorly understood, which limits treatment options and potential interventions for people living with HIV (PLWH). Elucidating the underlying pathophysiology of NRTI-induced ATN will facilitate the development of effective treatment strategies and improved patient outcomes. In this article, we will comprehensively review ATN in the setting of NRTI treatment for HIV infection. Full article
(This article belongs to the Special Issue New Insights into Transporters in Drug Development)
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12 pages, 243 KiB  
Review
Innovative Approaches to Optimize Clinical Transporter Drug–Drug Interaction Studies
by Sabina Paglialunga, Natacha Benrimoh and Aernout van Haarst
Pharmaceutics 2024, 16(8), 992; https://doi.org/10.3390/pharmaceutics16080992 - 26 Jul 2024
Cited by 3 | Viewed by 1677
Abstract
Of the 450 cell membrane transporters responsible for shuttling substrates, nutrients, hormones, neurotransmitters, antioxidants, and signaling molecules, approximately nine are associated with clinically relevant drug–drug interactions (DDIs) due to their role in drug and metabolite transport. Therefore, a clinical study evaluating potential transporter [...] Read more.
Of the 450 cell membrane transporters responsible for shuttling substrates, nutrients, hormones, neurotransmitters, antioxidants, and signaling molecules, approximately nine are associated with clinically relevant drug–drug interactions (DDIs) due to their role in drug and metabolite transport. Therefore, a clinical study evaluating potential transporter DDIs is recommended if an investigational product is intestinally absorbed, undergoes renal or hepatic elimination, or is suspected to either be a transporter substrate or perpetrator. However, many of the transporter substrates and inhibitors administered during a DDI study also affect cytochrome P450 (CYP) activity, which can complicate data interpretation. To overcome these challenges, the assessment of endogenous biomarkers can help elucidate the mechanism of complex DDIs when multiple transporters or CYPs may be involved. This perspective article will highlight how creative study designs are currently being utilized to address complex transporter DDIs and the role of physiology-based -pharmacokinetic (PBPK) models can play. Full article
(This article belongs to the Special Issue New Insights into Transporters in Drug Development)
16 pages, 937 KiB  
Review
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 2059
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 [...] Read more.
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  
Review
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
Cited by 1 | Viewed by 2057
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 [...] Read more.
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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