PDZK1 Regulates Two Intestinal Solute Carriers (Slc15a1 and Slc22a5) in Mice

Sugiura, Tomoko; Kato, Yukio; Wakayama, Tomohiko; Silver, David L.; Kubo, Yoshiyuki; Iseki, Shoichi; Tsuji, Akira

doi:10.1124/dmd.107.020321

Cited by 51 publications

(61 citation statements)

References 36 publications

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“…Male mice were used at 7 to 9 weeks of age. Transporter adaptor PDZK1 gene knockout [pdzk1(Ϫ/Ϫ)] mice were constructed previously and bred in the Institute for Experimental Animals, Kanazawa University, as described previously (Sugiura et al, 2008). All animals were maintained under standard conditions with a reverse light/dark cycle and were treated humanely.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Hepatic Uptake of Eltrombopag, a Novel Platelet-Increasing Agent

Takeuchi

Sugiura²,

Umeda³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Eltrombopag (ELT) is a novel thrombopoietin receptor agonist for the treatment of idiopathic thrombocytopenic purpura. Previous reports indicate that ELT is mainly eliminated in the liver, although its pharmacokinetic profile has not yet been clarified in detail. The purpose of the present study is to investigate the overall elimination mechanism of ELT. After intravenous administration of ELT to rats, approximately 40% of unchanged ELT was excreted into the bile in 72 h, whereas less than 0.02% of the dose was excreted in urine, indicating that liver is the major elimination organ for ELT. The total clearance was much lower than the hepatic blood flow rate and comparable with hepatic uptake clearance obtained from integration plot analysis. Coadministration of rifampicin, an organic anion transporter inhibitor, reduced both total clearance and hepatic uptake clearance of ELT. These results suggest that hepatic uptake is the rate-limiting process in the overall elimination of ELT. To further characterize the uptake mechanism, uptake of ELT by freshly isolated mouse hepatocytes was examined. The ELT uptake showed concentration and energy dependence and was inhibited by various compounds, including not only organic anions but also organic cations. Hepatic uptake clearance in vivo was reduced by coadministration of an organic cation, tetrapentylammonium. Finally, uptake of ELT was observed in human embryonic kidney 293 cells transfected with human hepatic transporters organic anion-transporting polypeptide (OATP) 1B1 and OATP2B1 and organic cation transporter OCT1. These results suggest that multiple transporters, including organic anion transporters and organic cation transporters, are involved in hepatic ELT uptake.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Hepatic Uptake of Eltrombopag, a Novel Platelet-Increasing Agent

Takeuchi

Sugiura²,

Umeda³

et al. 2011

Drug Metab Dispos

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“…The specimens were examined with a confocal laser scanning fluorescence microscope (LSM 510; Carl Zeiss, Jena, Germany). Mouse intestinal brush-border membrane vesicles (BBMVs) were prepared according to the previous study (Sugiura et al, 2008). Hepatic NPC, PC, and HEK293/OCTN1 cells were obtained as described above.…”

Section: Uptake Of [ 3 H]ergo By Everted Intestinal Sacmentioning

confidence: 99%

Functional Expression of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Mouse Small Intestine and Liver

et al. 2010

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ABSTRACT:Carnitine/organic cation transporter (OCTN1/SLC22A4) accepts various therapeutic agents as substrates in vitro and is expressed ubiquitously, although its function in most organs has not yet been examined. The purpose of the present study was to evaluate functional expression of OCTN1 in small intestine and liver, using octn1 gene knockout [octn1(؊/؊)] mice. After oral administration of [

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“…PDZK1 physically interacts with PEPT1 and OCTN2 (Kato et al, 2006;Sugiura et al, 2008), whereas it is not known whether a direct interaction of PEPT1 and SGLT1 with Rab8 occurs. Thus, the molecular mechanisms of apical localization of small intestinal transporters have recently been at least partly revealed, and not only transporter but also the intracellular sorting machinery proteins could have a significant influence on drug absorption.…”

Section: Discussionmentioning

confidence: 99%

“…We recently proposed that both PEPT1 and carnitine/organic cation transporter (OCTN2/Slc22a5) are regulated by a postsynaptic density 95/disc-large/zona occludens (PDZ) domain-containing scaffold protein, PDZK1, because the expression and apical localization of both transporters are down-regulated in small intestine of pdzk1 knockout mice, leading to delayed oral absorption of substrate drugs of PEPT1 and OCTN2 (Sugiura et al, 2008). PDZK1 physically interacts with PEPT1 and OCTN2 (Kato et al, 2006;Sugiura et al, 2008), whereas it is not known whether a direct interaction of PEPT1 and SGLT1 with Rab8 occurs.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Role of Oligopeptide Transporter PEPT1 and Sodium/Glucose Cotransporter SGLT1 in Intestinal Absorption of Their Substrates Using Small GTP-Binding Protein Rab8-Null Mice

Kato

Sugiura²,

Nakadera³

et al. 2008

Drug Metab Dispos

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ABSTRACT:A small GTP-binding protein, Rab8, is essential for apical localization of oligopeptide transporter PEPT1/SLC15A1 and sodium/glucose cotransporter SGLT1/SLC5A1 in small intestine; deficiency of rab8 gene results in mislocalization and reduced expression of these transporters. Here, we examined the role of PEPT1 and SGLT1 in vivo in gastrointestinal absorption of a ␤-lactam antibiotic, cefixime, and ␣-methyl-d-glycopyranoside (␣-MDG), respectively, using rab8 gene knockout [rab8(؊/؊)] mice as experimental animals deficient in those transporters. Plasma concentration of cefixime and ␣-MDG after oral administration in rab8(؊/؊) mice was much lower than that in wild-type mice, whereas such reduction in oral absorption was not observed for antipyrine, membrane permeation of which is not transporter-mediated. Uptake of cefixime from the apical side of isolated small intestine assessed by means of the everted sac method in wild-type mice was decreased in the presence of excess unlabeled glycylsarcosine, a PEPT1 substrate. In contrast, the uptake in rab8(؊/؊) mice was much lower than that in wild-type mice and comparable with that of an extracellular marker, mannitol, suggesting that the apical membrane permeability of cefixime was reduced in rab8(؊/؊) mice. Uptake of cefixime in wild-type mice was pH-dependent, being higher at lower pH, whereas that in rab8(؊/؊) mice remained at the background level at all pH values examined. These results suggest that PEPT1 and SGLT1 play an important role in gastrointestinal absorption of cefixime and ␣-MDG, respectively, in vivo in mice. The present findings also illustrate the pharmacokinetic influence of the sorting machinery protein Rab8.

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PDZK1 Regulates Two Intestinal Solute Carriers (Slc15a1 and Slc22a5) in Mice

Cited by 51 publications

References 36 publications

Pharmacokinetics and Hepatic Uptake of Eltrombopag, a Novel Platelet-Increasing Agent

Pharmacokinetics and Hepatic Uptake of Eltrombopag, a Novel Platelet-Increasing Agent

Functional Expression of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Mouse Small Intestine and Liver

Investigation of the Role of Oligopeptide Transporter PEPT1 and Sodium/Glucose Cotransporter SGLT1 in Intestinal Absorption of Their Substrates Using Small GTP-Binding Protein Rab8-Null Mice

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