Involvement of Organic Cation Transporter 1 in Hepatic and Intestinal Distribution of Metformin

Wang, Desheng; Jonker, Johan W.; Kato, Yukio; Kusuhara, Hiroyuki; Schinkel, Alfred H.; Sugiyama, Yuichi

doi:10.1124/jpet.102.034140

Cited by 401 publications

(333 citation statements)

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“…[22][23][24][25] Our transport studies identify metformin as an OCT3 substrate (Fig. 4) with an affinity for OCT3 similar to that for OCT1 21,28,29 and a twofold higher maximal transport rate compared with OCT1. Recently, Shu et al 29,33 showed significant alteration of pharmacokinetics of metformin and its glucose-lowering effect in individuals with reduced-function OCT1 variants.…”

Section: Discussionmentioning

confidence: 99%

“…27 The impact of an altered OCT1-mediated drug transport on pharmacokinetics can be exemplified by metformin. In Oct1 ϩ/ϩ mice, the liver concentration of metformin was approximately 30 times higher than in Oct1 Ϫ/Ϫ mice; 28 moreover, the blood glucose-lowering effect of metformin was completely abolished in Oct1 Ϫ/Ϫ mice. 29 In humans, several OCT1 variants with reduced transport function, including metformin transport, have been identified.…”

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confidence: 89%

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Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver†

et al. 2009

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An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrixassisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide singlenucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/ OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113-and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P < 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P ‫؍‬ 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 89%

Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver†

et al. 2009

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“…Hepatic uptake of small organic cations includes essential substrates for biosynthetic pathways as well as xenobiotics and is of major importance because the liver represents the main site for biotransformation in the body. For example, hepatic uptake of metformin in Oct1 knockout mice is reduced more than 30 times below levels of uptake in wild-type mice, 35 and results in lower blood concentrations of lactate. 36 Transport of metformin into the liver is essential for its antidiabetic effect that is mediated by inhibition of complex 1 of the mitochondrial respiratory chain in the hepatocyte.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis

et al. 2004

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The liver plays a major role in biotransformation and elimination of various therapeutic agents and xenobiotics, many of which are organic cations and substrates of the organic cation transporter 1 (Oct1, Slc22a1). Oct1 is expressed at the basolateral membranes of hepatocytes and proximal renal tubules. Although Oct1 is the major uptake mechanism in hepatocytes for many pharmaceutical compounds, little is known about the effects of liver injury on this process. Our aim was to investigate the effects of obstructive cholestasis on Oct1 expression and function in liver and kidney. The effects of bile duct ligation (BDL) on Oct1 protein, messenger RNA (mRNA) expression, and tissue localization were determined in rat liver and kidney with Western analysis, real-time reverse transcriptase-mediated polymerase chain reaction (RT-PCR), and immunofluorescence. To assess Oct1 function, the model substrate tetraethylammonium ([ 14 C]TEA) was administered intravenously to BDL and control rats and distribution of radioactivity was determined. Oct1 protein significantly decreased in cholestatic livers to 42.1 ؎ 17.7% (P < .001), 15.5 ؎ 4.7% (P < .05), and 8.6 ؎ 2.7% (P < .05) of controls after 3, 7, and 14 days, respectively, but not in kidneys. Hepatic Oct1 mRNA decreased to 77.2 ؎ 12.7%, 40.7 ؎ 8.1% (P < .05), and 50.3 ؎ 7.5% (P < .05) 3, 7, and 14 days after BDL, respectively. Tissue immunofluorescence corroborated these data. Hepatic accumulation of [ 14 C]TEA in 14-day BDL rats was reduced to 29.6 ؎ 10.9% of controls (P < .0005). In conclusion, obstructive cholestasis down-regulates Oct1 and impairs Oct1-mediated uptake in rat liver, suggesting that hepatic uptake of small cationic drugs may be impaired in cholestatic liver injury. (HEPATOLOGY 2004;39:1382-1389

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“…OCT1 and OCT3 are expressed on the sinusoidal membrane of hepatocytes and play a major role in the uptake of metformin from blood into the hepatocytes 59 . In 2002, elegant studies from the Sugiyama group showed that OCT1 is responsible for the hepatic uptake and intestinal distribution of metformin 60,61 Further, reduced hepatic metformin concentrations have been shown to affect metformin response in mice 62 . In particular, the hepatic accumulation of metformin was significantly greater in wildtype mice than in Oct1 knockout mice after a single oral dose of the drug.…”

Section: Transporters Involved In Metformin Pharmacologic Actionmentioning

confidence: 99%

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

Liang

Giacomini

2017

Journal of Pharmaceutical Sciences

131

113

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Metformin, widely used as first-line treatment for type 2 diabetes, exists primarily as a hydrophilic cation at physiological pHs. As such, membrane transporters play a substantial role in its absorption, tissues distribution, and renal elimination. Multiple organic cation transporters are determinants of the pharmacokinetics of metformin, and many of them are important in its pharmacological action, as mediators of metformin entry into target tissues. Further, a recent genomewide association study (GWAS) in a large multi-ethnic population implicated polymorphisms in SLC2A2, encoding the glucose transporter, GLUT2, as important determinants of response to metformin. Here, we describe the key transporters associated with metformin pharmacokinetics and response.

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Involvement of Organic Cation Transporter 1 in Hepatic and Intestinal Distribution of Metformin

Cited by 401 publications

References 32 publications

Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver†

Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver†

Down-regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

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