Testicular disposition of clofarabine in rats is dependent on equilibrative nucleoside transporters

Miller, Siennah R.; Jilek, Joseph L.; McGrath, Meghan E.; Hau, Raymond K.; Jennings, Erin Q.; Galligan, James J.; Wright, Stephen H.; Cherrington, Nathan J.

doi:10.1002/prp2.831

Cited by 4 publications

(17 citation statements)

References 71 publications

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“…Rats were dosed nitrobenzylthioinosine‐P, the phosphorylated prodrug of nitrobenzylthioinosine, via intraperitoneal injection at 10 mg/kg in 7.5% dimethylsulfoxide in sterile saline or vehicle 20 minutes before clofarabine, lamivudine, or vehicle control dosing. This was followed by dosing with clofarabine at a dose that would achieve detectable levels of compound in plasma and testes or at a therapeutically relevant dose based on preliminary experiments 82 . A second group dosed with lamivudine, which is known to not interact with the ENTs, was included as a control.…”

Section: Modeling Ent1‐mediated and Ent2‐mediated Transport And Dispo...mentioning

confidence: 99%

“…This was followed by dosing with clofarabine at a dose that would achieve detectable levels of compound in plasma and testes or at a therapeutically relevant dose based on preliminary experiments. 82 A second group dosed with lamivudine, which is known to not interact with the ENTs, was included as a control. The plasma concentrations of nitrobenzylthioinosine and each probe drug were monitored in addition to testicular tissue concentrations.…”

Section: Modeling Ent1-mediated and Ent2-mediated Transport And Dispo...mentioning

confidence: 99%

“…Clofarabine is typically used to treat pediatric patients with refractory or relapsed acute lymphoid/myeloid leukemias 82 and has the potential to cross the blood‐testis barrier through the ENT1 and ENT2 transepithelial transport pathway ( Figure ) 36 . Clofarabine is a documented ENT substrate and inhibitor, 33,89 and has been used as a probe ENT substrate to demonstrate the contribution of ENTs to the testicular disposition of clofarabine in Sertoli cells and in rats 82 . In Miller et al ., 82 after observing a decrease in clofarabine uptake in the presence or absence of nitrobenzylthioinosine using in vitro models, the in vivo disposition of that molecule across the rat blood‐testis barrier was further explored.…”

Section: Modeling Ent1‐mediated and Ent2‐mediated Transport And Dispo...mentioning

confidence: 99%

“…Because the ENTs can facilitate the disposition of antineoplastic and antiviral therapeutics, they can be used to deliver therapeutics for the treatment of viral infections (e.g., human immunodeficiency, Zika, Ebola, and SARS-CoV-2 viruses) and refractory or relapsing cancers (e.g., leukemias) in pharmacological and immunological sanctuary sites like the testes. [84][85][86][87][88] Clofarabine is typically used to treat pediatric patients with refractory or relapsed acute lymphoid/myeloid leukemias 82 and has the potential to cross the blood-testis barrier through the ENT1 and ENT2 transepithelial transport pathway (Figure 1e). 36 Clofarabine is a documented ENT substrate and inhibitor, 33,89 and has been used as a probe ENT substrate to demonstrate the contribution of ENTs to the testicular disposition of clofarabine in Sertoli cells and in rats.…”

Section: Modeling Ent1-mediated and Ent2-mediated Transport And Dispo...mentioning

confidence: 99%

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Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development

Hau

Wright

Cherrington

2023

Clin Pharma and Therapeutics

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The US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) guidances on small‐molecule drug–drug interactions (DDIs), with input from the International Transporter Consortium (ITC), recommend the evaluation of nine drug transporters. Although other clinically relevant drug uptake and efflux transporters have been discussed in ITC white papers, they have been excluded from further recommendation by the ITC and are not included in current regulatory guidances. These include the ubiquitously expressed equilibrative nucleoside transporters (ENT) 1 and ENT2, which have been recognized by the ITC for their potential role in clinically relevant nucleoside analog drug interactions for patients with cancer. Although there is comparatively limited clinical evidence supporting their role in DDI risk or other adverse drug reactions (ADRs) compared with the nine highlighted transporters, several in vitro and in vivo studies have identified ENT interactions with non‐nucleoside/non‐nucleotide drugs, in addition to nucleoside/nucleotide analogs. Some noteworthy examples of compounds that interact with ENTs include cannabidiol and selected protein kinase inhibitors, as well as the nucleoside analogs remdesivir, EIDD‐1931, gemcitabine, and fialuridine. Consequently, DDIs involving the ENTs may be responsible for therapeutic inefficacy or off‐target toxicity. Evidence suggests that ENT1 and ENT2 should be considered as transporters potentially involved in clinically relevant DDIs and ADRs, thereby warranting further investigation and regulatory consideration.

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Section: Modeling Ent1‐mediated and Ent2‐mediated Transport And Dispo...mentioning

confidence: 99%

Section: Modeling Ent1-mediated and Ent2-mediated Transport And Dispo...mentioning

confidence: 99%

Section: Modeling Ent1‐mediated and Ent2‐mediated Transport And Dispo...mentioning

confidence: 99%

Section: Modeling Ent1-mediated and Ent2-mediated Transport And Dispo...mentioning

confidence: 99%

See 2 more Smart Citations

Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development

Hau

Wright

Cherrington

2023

Clin Pharma and Therapeutics

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“…It is also known to cause toxicities in many organs, including in the seminiferous tubules of rodents and canines (U.S. Food and Drug Administration, 2004). Clofarabine has been shown to be a substrate of ENT1 and ENT2, and its disposition across the in vivo rat BTB is dependent on the ENTs (Miller et al, 2021a). In addition to SC expression, ENT1 and ENT2 are expressed by rat and human LCs and developing germ cells, which would support normal cellular growth and health.…”

Section: Nucleoside Transportersmentioning

confidence: 99%

Drug Transporters at the Human Blood-Testis Barrier

2023

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Transporters are involved in the movement of many physiologically important molecules across cell membranes and have a substantial impact on the pharmacological and toxicological effect of xenobiotics. Many transporters have been studied in the context of disposition to, or toxicity in, organs like the kidney and liver; however, transporters in the testes are increasingly gaining recognition for their role in drug transport across the blood-testis barrier (BTB). The BTB is an epithelial membrane barrier formed by adjacent Sertoli cells (SCs) in the seminiferous tubules that form intercellular junctional complexes to protect developing germ cells from the external environment. Consequently, many charged or large polar molecules cannot cross this barrier without assistance from a transporter. SCs express a variety of drug uptake and efflux transporters to control the flux of endogenous and exogenous molecules across the BTB. Recent studies have identified several transport pathways in SCs that allow certain drugs to circumvent the human BTB. These pathways may exist in other species, such as rodents and nonhuman primates; however, there is (1) a lack of information on their expression and/or localization in these species and (2) conflicting reports on localization of some transporters that have been evaluated in rodents compared to humans. This review outlines the current knowledge on the expression and localization of pharmacologically relevant drug transporters in human testes and calls attention to the insufficient and contradictory understanding of testicular transporters in other species that are commonly used in drug disposition and toxicity studies.

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Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis Barrier

et al. 2022

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The blood-testis barrier (BTB) is formed by basal tight junctions between adjacent Sertoli cells (SCs) of the seminiferous tubules and acts as a physical barrier to protect developing germ cells in the adluminal compartment from reproductive toxicants. Xenobiotics, including antivirals, male contraceptives, and cancer chemotherapeutics, are known to cross the BTB, although the mechanisms that permit barrier circumvention are generally unknown. This study used immunohistological staining of human testicular tissue to determine the site of expression for xenobiotic transporters that facilitate transport across the BTB. Organic anion transporter (OAT) 1, OAT2, and organic cation transporter, novel (OCTN) 1 primarily localized to the basal membrane of SCs, whereas OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7 localized to SC basal membranes and peritubular myoid cells (PMCs) surrounding the seminiferous tubules. Concentrative nucleoside transporter (CNT) 2 localized to Leydig cells (LCs), PMCs, and SC apicolateral membranes. Organic cation transporter (OCT) 1, OCT2, and OCT3 mostly localized to PMCs and LCs, although there was minor staining in developing germ cells for OCT3. Organic anion transporting polypeptide (OATP) 1A2, OATP1B1, OATP1B3, OATP2A1, OATP2B1, and OATP3A1-v2 localized to SC basal membranes with diffuse staining for some transporters. Notably, OATP1C1 and OATP4A1 primarily localized to LCs. Positive staining for multidrug and toxin extrusion protein (MATE) 1 was only observed throughout the adluminal compartment. Definitive staining for CNT1, OAT3, MATE2, and OATP6A1 was not observed. The location of these transporters is consistent with their involvement in the movement of xenobiotics across the BTB. Altogether, the localization of these transporters provides insight into the mechanisms of drug disposition across the BTB and will be useful in developing tools to overcome the pharmacokinetic and pharmacodynamic difficulties presented by the BTB. SIGNIFICANCE STATEMENTAlthough the total mRNA and protein expression of drug transporters in the testes has been explored, the localization of many transporters at the blood-testis barrier (BTB) has not been determined. This study applied immunohistological staining in human testicular tissues to identify the cellular localization of drug transporters in the testes. The observations made in this study have implications for the development of drugs that can effectively use transporters expressed at the basal membranes of Sertoli cells to bypass the BTB.

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Testicular disposition of clofarabine in rats is dependent on equilibrative nucleoside transporters

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 4 publications

References 71 publications

Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development

Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development

Drug Transporters at the Human Blood-Testis Barrier

Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis Barrier

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