Expression Levels of Renal Organic Anion Transporters (OATs) and Their Correlation with Anionic Drug Excretion in Patients with Renal Diseases

Sakurai, Yuji; Motohashi, Hideyuki; Ueo, Harumasa; Masuda, Satohiro; Saya, Hideyuki; Okuda, Masahiro; Mori, Noriko; Matsuura, Motokazu; Doi, Toshio; Fukatsu, Atsushi; Ogawa, Osamu; Inui, Ken Ichi

doi:10.1023/b:pham.0000012153.71993.cb

Cited by 98 publications

(81 citation statements)

References 27 publications

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“…One of the first post-OAT-cloning studies evaluating OAT regulation by renal disease reported that patients with several forms of renal disease, when assessed as a group, exhibited reduced renal cortical hOAT1 mRNA levels [114]. In addition, although hOAT3 mRNA levels were unaltered in patients with renal disease, elimination of the b-lactam antibiotic cefazolin exhibited a significant correlation with renal hOAT3 mRNA levels.…”

Section: Phosphorylationmentioning

confidence: 99%

“…In addition, although hOAT3 mRNA levels were unaltered in patients with renal disease, elimination of the b-lactam antibiotic cefazolin exhibited a significant correlation with renal hOAT3 mRNA levels. Cefazolin was confirmed as a substrate for hOAT3 in HEK293 cells [114]. Further studies examined the effect of bilateral ureteral obstruction (BUO) in rats [115].…”

Section: Phosphorylationmentioning

confidence: 99%

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Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

VanWert

Gionfriddo

Sweet

2009

Biopharm & Drug Disp

219

238

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Our understanding of the mechanisms behind inter-and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with organic anion transporters (OATs). Collectively, these transporters are nearly ubiquitously expressed in barrier epithelia. Moreover, several reports indicate that OATs are subject to diverse forms of regulation, much like drug metabolizing enzymes and receptors. Thus, critical to furthering our understanding of patient-and condition-specific responses to pharmacotherapy is the complete characterization of OAT interactions with drugs and regulatory factors. This review provides the reader with a comprehensive account of the function and substrate profile of cloned OATs. In addition, a major focus of this review is on the regulation of OATs including the impact of transcriptional and epigenetic factors, phosphorylation, hormones and gender.

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Section: Phosphorylationmentioning

confidence: 99%

Section: Phosphorylationmentioning

confidence: 99%

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

VanWert

Gionfriddo

Sweet

2009

Biopharm & Drug Disp

219

238

View full text Add to dashboard Cite

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“…The mRNA expression levels of OCT2 and OAT1-4 were quantified as described previously (Motohashi et al 2002;Sakurai et al 2004). Briefly, total RNA was isolated from specimens using a MagNA Pure LC RNA isolation Kit II (Roche Diagnostic GmbH, Mannheim, Germany) and was reverse transcribed to yield complementary DNA (cDNA).…”

Section: Quantification Of Oct2 and Oat1-4 Mrna Expressionmentioning

confidence: 99%

“…It has been demonstrated that variations in the expression levels of SLC22A are responsible for the individual variations in pharmacokinetics by clinical studies (Sakurai et al 2004(Sakurai et al , 2005 and in vivo animal experiments (Ji et al 2002;Deguchi et al 2005). For example, we previously reported that the messenger ribonucleic acid (mRNA) level of OAT3 among OAT1-4 significantly correlated with the elimination rates of cefazolin and phenolsulfonphthalein in patients with renal diseases (Sakurai et al 2004(Sakurai et al , 2005.…”

Section: Introductionmentioning

confidence: 99%

“…For example, we previously reported that the messenger ribonucleic acid (mRNA) level of OAT3 among OAT1-4 significantly correlated with the elimination rates of cefazolin and phenolsulfonphthalein in patients with renal diseases (Sakurai et al 2004(Sakurai et al , 2005. However, factors regulating the interindividual differences in mRNA levels of transporters have not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney

et al. 2008

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Organic cation transporters (OCTs) and organic anion transporters (OATs) (SLC22A family) play crucial roles in the renal secretion of various drugs. Messengar ribonucleic acid (mRNA) expression of transporters can be a key factor regulating interindividual differences in drug pharmacokinetics. However, the source of variations in mRNA levels of transporters is unclear. In this study, we focused on single nucleotide polymorphisms (SNP) in the promoter region [regulatory SNPs (rSNPs)] as candidates for the factor regulating mRNA levels of SLC22A. We sequenced the promoter regions of OCT2 and OAT1-4 in 63 patients and investigated the effects of the identified rSNPs on transcriptional activities and mRNA expression. In the OCT2 promoter region, one deletion polymorphism (-578_-576delAAG) was identified; -578_-576delA-AG significantly reduced OCT2 promoter activity (p \ 0.05), and carriers of -578_-576delAAG tend to have lower OCT2 mRNA levels, but the difference is not significant. There was no rSNP in the OAT1 and OAT2 genes. The five rSNPs of OAT3 and one rSNP of OAT4 were unlikely to influence mRNA expression and promoter activity. This is the first study to investigate the influences of rSNPs on mRNA expression of SLC22A in the kidney and to identify a regulatory polymorphism affecting OCT2 promoter activity.

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OATP1A2, OAT1, and OAT3

Tirona¹

2013

Pharmacogenomics of Human Drug Transporters

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Expression Levels of Renal Organic Anion Transporters (OATs) and Their Correlation with Anionic Drug Excretion in Patients with Renal Diseases

Abstract: These results suggest that hOAT3 plays an important role for anionic drug secretion in patients with renal diseases and that the expression levels of drug transporters may be related to the alteration of renal drug secretion.

Cited by 98 publications

References 27 publications

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney

OATP1A2, OAT1, and OAT3

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