OCT (SLC22A) and OCTN Family

Stocker, Sophie L.; Riedmaier, Arian Emami; Schwab, Matthias; Giacomini, Kathleen M.

doi:10.1002/9781118353240.ch8

Cited by 6 publications

(10 citation statements)

References 150 publications

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“…The experiments were also performed in the presence of known OCT inhibitors. TBA + was used to inhibit OCT1 and OCT2 uptake (9), irinotecan was used to inhibit OCT3 uptake (33), and L-carnitine was used to inhibit OCTN1 and OCTN2 uptake (34).…”

Section: Amisulpride and Sulpiride As Substrates Of Slc22 Cation Tranmentioning

confidence: 99%

The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpiride Are Substrates of the Organic Cation Transporters from the SLC22 Family

Pereira

Tadjerpisheh

Abed

et al. 2014

AAPS J

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Abstract. Variations in influx transport at the blood-brain barrier might affect the concentration of psychotropic drugs at their site of action and as a consequence might alter therapy response. Furthermore, influx transporters in organs such as the gut, liver and kidney may influence absorption, distribution, and elimination. Here, we analyzed 30 commonly used psychotropic drugs using a parallel artificial membrane permeability assay. Amisulpride and sulpiride showed the lowest membrane permeability (P e <1.5×10−6 cm/s) and will require influx transport to penetrate the blood-brain barrier and other physiological barriers. We then studied the uptake of amisulpride and sulpiride by the organic cation transporters of the SLC22 family OCT1, OCT2, OCT3, OCTN1, and OCTN2 Amisulpride was found to be transported by all five transporters studied. In contrast, sulpiride was only transported by OCT1 and OCT2. OCT1 showed the highest transport ability both for amisulpride (CL int =1.9 ml/min/mg protein) and sulpiride (CL int =4.2 ml/min/mg protein) and polymorphisms in OCT1 significantly reduced the uptake of both drugs. Furthermore, we observed carrier-mediated uptake that was inhibitable by known OCT inhibitors in the immortalized human brain microvascular endothelial cell line hCMEC/D3. In conclusion, this study demonstrates that amisulpride and sulpiride are substrates of organic cation transporters of the SLC22 family. SLC22 transporters may play an important role in the distribution of amisulpride and sulpiride, including their ability to penetrate the blood-brain barrier.

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Section: Amisulpride and Sulpiride As Substrates Of Slc22 Cation Tranmentioning

confidence: 99%

The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpiride Are Substrates of the Organic Cation Transporters from the SLC22 Family

Pereira

Tadjerpisheh

Abed

et al. 2014

AAPS J

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“…[1][2][3][4][5] A large number of functional in vitro studies, as well as, pharmacogenetic studies clearly indicate an important role of SLC22 transporter proteins (for example, SLC22A5/OCTN2, SLC22A12/URAT1) in absorption, distribution and elimination of a diverse group of endogenous compounds and of drugs. [1][2][3][4][5] The organic anion transporter 7 (OAT7, encoded by SLC22A9) is so far poorly characterized. Since its initial discovery in 2007 as a novel liver-specific transporter localized to the sinusoidal hepatocyte membrane, 6 further functional characterization and studies on the inter-individual variability of its hepatic expression have not been undertaken.…”

Section: Introductionmentioning

confidence: 99%

Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors

et al. 2015

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Human organic anion transporter 7 (OAT7, SLC22A9) is a hepatic transport protein poorly characterized so far. We therefore sought to identify novel OAT7 substrates and factors contributing to variable hepatic OAT7 expression. Using OAT7-expressing cells, pravastatin was identified as a substrate. Hepatic SLC22A9/OAT7 mRNA and protein expression varied 28-fold and 15-fold, respectively, in 126 Caucasian liver samples. Twenty-four variants in SLC22A9 were genotyped, including three rare missense variants (rs377211288, rs61742518, rs146027075), which occurred only heterozygously. No variant significantly affected hepatic SLC22A9/OAT7 expression. The three missense variants, however, showed functional consequences when expressed in vitro. Hepatic nuclear factor 4-alpha (HNF4α) emerged as a major transcriptional regulator of SLC22A9 by a series of in silico and in vitro analyses. In conclusion, pravastatin is the first identified OAT7 drug substrate. Substantial inter-individual variability in hepatic OAT7 expression, majorly driven by HNF4α, may contribute to pravastatin drug disposition and might affect response.The Pharmacogenomics Journal advance online publication, 4 August 2015; doi:10.1038/tpj.2015.55.

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“…SLC22A1 c.1222A>G (rs628031) is found in 74% of African American, 60% of white American, and 74% to 80% of Asian individuals . Although in vitro studies did not correlate with reduced uptake of metformin in transfected HEK293 cells, a small study in 33 patients with type 2 diabetes on metformin revealed that the variant allele was a positive predictor of metformin efficacy .…”

Section: Slc Transporter Polymorphisms Of Potential Clinical Significmentioning

confidence: 98%

“…The prevalence of these 2 polymorphisms is variable depending on the ethnic group being evaluated. SLC22A1 p.M420del is more commonly seen in white (18.5%) and Mexican (21.4%) Americans than in African Americans (2.9%), whereas c.181C>T is less prevalent with frequencies of 7.2% and 5.6% for white and Mexican Americans, respectively . Furthermore, the presence of variant SLC22A1 p.M420del in KCL22‐hOCT1 cells was also associated with reduced imatinib uptake, although the effect was obliterated in the presence of SLC22A1 c.1222A>G (rs628031) .…”

Section: Slc Transporter Polymorphisms Of Potential Clinical Significmentioning

confidence: 99%

“…In comparison to SLC22A1 , few variants within SLC22A2 have been assessed for drug associations. However, SLC22A2 c.808G>T (rs316019), which has an overall prevalence of approximately 7% to 16%, has been associated with decreased metformin transport in vitro . Moreover, Song et al determined that the SLC22A2 c.808G>T variant was associated with increased metformin AUC and decreased renal clearance in healthy Korean individuals .…”

Section: Slc Transporter Polymorphisms Of Potential Clinical Significmentioning

confidence: 99%

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Impact of Transporter Polymorphisms on Drug Development: Is It Clinically Significant?

McLean

Wilson

Kim

2016

The Journal of Clinical Pharma

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Drug transporters are becoming increasingly recognized as relevant to the drug development process. This may be a reflection of increasing target complexity and the need for high-affinity interaction with drug targets that minimize off-target side effects. Moreover, as new molecular entities (NMEs) become larger in size and amphipathic in nature, interaction with drug transporters, both uptake as well as efflux, becomes increasingly likely. In some cases transporters may limit the absorption or organ-specific entry of NMEs, whereas in other cases transporters may enhance their absorption or tissue accumulation. Indeed, in some cases, transporters may prove to be a therapeutic target. Accordingly, a better understanding of potentially clinically relevant drug transporter polymorphisms earlier in the drug development process is highly desirable. In this review we examine key transporters that are important to the absorption, distribution, and excretion of a large number of drugs in clinical use. Importantly, we provide our assessment of the potential impact of known polymorphisms in such transporters and discuss whether there is sufficient evidence to incorporate these polymorphisms in the drug development process.

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OCT (SLC22A) and OCTN Family

Cited by 6 publications

References 150 publications

The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpiride Are Substrates of the Organic Cation Transporters from the SLC22 Family

The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpiride Are Substrates of the Organic Cation Transporters from the SLC22 Family

Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors

Impact of Transporter Polymorphisms on Drug Development: Is It Clinically Significant?

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