Rat Kidney Slices for Evaluation of Apical Membrane Transporters in Proximal Tubular Cells

Arakawa, Hiroshi; Kubo, Hikaru; Washio, Ikumi; Staub, Angelina Yukiko; Nedachi, Shiho; Ishiguro, Naoki; Nakanishi, Takeo; Tamai, Ikumi

doi:10.1016/j.xphs.2019.03.031

Cited by 13 publications

(9 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Culture fibroblasts, vascular endothelial cells, HeLa cells, and hepatocytes are all easily cultured on HCF. [14][15][16][17] In addition, HCF may promote tissue maturation by cell-cell interaction when co-cultured with cells on the other side of the film. In cellbased assays, the superior porosity and thickness of HCF can be expected to reduce any rate-determining effects of the filter membrane compared to conventional TEM such as Transwell ® .…”

Section: Introductionmentioning

confidence: 99%

Drug Transcellular Transport Assay Using a High Porosity Honeycomb Film

Nakazono

Arakawa

Nishino

et al. 2021

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

In vitro transport studies across cells grown on culture inserts are widely used for evaluating pharmacokinetic characteristics such as intestinal membrane permeability. However, measurements of the apparent permeability coefficient of highly lipophilic compounds are often limited by transport across the membrane filters, not by transport across the cultured cells. To overcome this concern, we have investigated the utility of a high-porosity membrane honeycomb film (HCF) for transcellular transport studies. Using the HCF inserts, the apparent permeability coefficient (P app ) of the drugs tested in LLC-PK1 and Caco-2 cells tended to increase with an increase in lipophilicity, reaching a maximum P app value at Log D higher than 2. In contrast, using the commercially available Track-Etched membrane (TEM) inserts, a maximum value was observed at Log D higher than 1. The basolateral to apical transport permeability P app(BL→AP) of rhodamine 123 across LLC-PK1 cells that express P-glycoprotein (P-gp) cultured on HCF inserts and TEM inserts was 2.33 and 2.39 times higher than the reverse directional P app(AP→BL) permeability, respectively. The efflux ratio (P app(B-A) / P app(A-B) ) of rhodamine 123 in LLC-PK1 expressing P-gp cells using HCF inserts was comparable to that obtained using TEM inserts, whereas the transported amount in both directions was significantly higher when using the HCF inserts. Accordingly, due to the higher permeability and high porosity of HCF membranes, it is expected that transcellular transport of high lipophilic as well as hydrophilic compounds and substrate recognition of transporters can be evaluated more accurately by using HCF inserts.

show abstract

Section: Introductionmentioning

confidence: 99%

Drug Transcellular Transport Assay Using a High Porosity Honeycomb Film

Nakazono

Arakawa

Nishino

et al. 2021

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

show abstract

“…Since the accessibility of drug molecules to intracellular enzymes depends on their ability to migrate into cells, we investigated the cell permeability and the intracellular accumulation of the Akt inhibitors and the DDCs using cancer cells. 34 Akt inhibitors A1-NH2 and A2-NH2 exhibited sufficient cell permeability [the apparent permeability coefficients (Papp) of 8.55 ± 0.87 × 10 −6 and 18.9 ± 3.2 × 10 −6 cm/sec, respectively, Fig. 3A] and accumulation values (cell to medium ratios) of 33.6 ± 0.3 and 31.1 ± 2.4 µL/cm 2 , respectively (Fig.…”

Section: Evaluation Of Cell Permeability and Intracellular Accumulationmentioning

confidence: 99%

Drug–drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers

Fujita,

Arai,

Arakawa

et al. 2023

Preprint

View full text Add to dashboard Cite

Controlling RAS mutant cancer progression remains a significant challenge in developing anticancer drugs. Whereas Ras G12C-covalent binders have received clinical approval, the emergence of further mutations, along with the activation of Ras-related proteins and signals, has led to resistance to Ras binders. To discover novel compounds to overcome this bottleneck, we focused on the concurrent and sustained blocking of two major signaling pathways downstream of Ras. To this end, we synthesized 25 drug–drug conjugates (DDCs) by combining the MEK inhibitor trametinib with Akt inhibitors using seven types of linkers with structural diversity. These DDCs were evaluated for their cell permeability/accumulation and ability to inhibit proliferation in RAS-mutant cell lines. A representative DDC was further evaluated for its effects on signaling proteins, induction of apoptosis-related proteins, and the stability of hepatic metabolic enzymes. These in vitro studies identified a series of DDCs, especially those containing a furan-based linker, with promising properties as agents for treating RAS-mutant cancers. Additionally, in vivo experiments in mice using the two selected DDCs revealed prolonged half-lives and anticancer efficacies comparable to those of trametinib. The DDCs developed in this study have potential as drug candidates for the broad inhibition of RAS-mutant cancers.

show abstract

“…The involvement of OCTN1 in paeonol transport to the retina across the iBRB has been investigated following the uptake of [ 3 H] paeonol by the conditionally immortalized rat retina capillary endothelial cells (TR-iBRB cell lines) used as an in vitro model of the iBRB. OCTN1 failed to transport paeonol [ 82 ]. Involvement of OCTN1 in absorption of naloxone and naltrexone, used to reverse opioid overdose, has been investigated.…”

Section: Interaction With Drugsmentioning

confidence: 99%

OCTN1: A Widely Studied but Still Enigmatic Organic Cation Transporter Linked to Human Pathology and Drug Interactions

Pochini

Galluccio

Scalise

et al. 2022

IJMS

View full text Add to dashboard Cite

The Novel Organic Cation Transporter, OCTN1, is the first member of the OCTN subfamily; it belongs to the wider Solute Carrier family SLC22, which counts many members including cation and anion organic transporters. The tertiary structure has not been resolved for any cation organic transporter. The functional role of OCNT1 is still not well assessed despite the many functional studies so far conducted. The lack of a definitive identification of OCTN1 function can be attributed to the different experimental systems and methodologies adopted for studying each of the proposed ligands. Apart from the contradictory data, the international scientific community agrees on a role of OCTN1 in protecting cells and tissues from oxidative and/or inflammatory damage. Moreover, the involvement of this transporter in drug interactions and delivery has been well clarified, even though the exact profile of the transported/interacting molecules is still somehow confusing. Therefore, OCTN1 continues to be a hot topic in terms of its functional role and structure. This review focuses on the most recent advances on OCTN1 in terms of functional aspects, physiological roles, substrate specificity, drug interactions, tissue expression, and relationships with pathology.

show abstract

Rat Kidney Slices for Evaluation of Apical Membrane Transporters in Proximal Tubular Cells

Cited by 13 publications

References 28 publications

Drug Transcellular Transport Assay Using a High Porosity Honeycomb Film

Drug Transcellular Transport Assay Using a High Porosity Honeycomb Film

Drug–drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers

OCTN1: A Widely Studied but Still Enigmatic Organic Cation Transporter Linked to Human Pathology and Drug Interactions

Contact Info

Product

Resources

About