OCT1 Polyspecificity—Friend or Foe?

Meyer, Marleen J.; Tzvetkov, Mladen V.

doi:10.3389/fphar.2021.698153

Cited by 9 publications

(5 citation statements)

References 51 publications

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Section: ■ Discussion and Conclusionmentioning

confidence: 99%

“…Altogether, with some substrate−transporter combinations, OCTs were capable of highly stereoselective substrate translocation, which was not expected considering the pronounced polyspecificity of OCTs. 36 study showed that there can be remarkable differences in stereospecificity between the three closely related transporters, and the stereospecificity of OCT2 and OCT3 appeared to be much more stereospecific than OCT1.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 90%

See 1 more Smart Citation

Stereoselectivity in Cell Uptake by SLC22 Organic Cation Transporters 1, 2, and 3

Gebauer,

Jensen,

Rafehi

et al. 2023

J. Med. Chem.

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Stereoselectivity can be most relevant in drug metabolism and receptor binding. Although drug membrane transport might be equally important for small-molecule pharmacokinetics, the extent of stereoselectivity in membrane transport is largely unknown. Here, we characterized the stereoselective transport of 18 substrates of SLC22 organic cation transporters (OCTs) 1, 2, and 3. OCT2 and OCT3 showed highly stereoselective cell uptake with several substrates and, interestingly, often with opposite stereoselectivity. In contrast, transport by OCT1 was less stereoselective, although ( R )-tamsulosin was transported by OCT1 with higher apparent affinity than the ( S )-enantiomer. Using OCT1 and CYP2D6 co-overexpressing cells, an additive effect of the stereoselectivities was demonstrated. This indicates that pharmacokinetic stereoselectivity may be the result of combined effects in transport and metabolism. This study highlights that the pronounced polyspecificity of OCTs not contradicts stereoselectivity in the transport. Nevertheless, stereoselectivity is highly substrate-specific and for most substrates and OCTs, there was no major selectivity.

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Section: ■ Discussion and Conclusionmentioning

confidence: 99%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 90%

Stereoselectivity in Cell Uptake by SLC22 Organic Cation Transporters 1, 2, and 3

Gebauer,

Jensen,

Rafehi

et al. 2023

J. Med. Chem.

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“…Metformin enters the liver via OCT1 and OCT3, where it suppresses gluconeogenesis. Multi-specificity is one of the most distinguishing features of OCT1 (Meyer and Tzvetkov, 2021). Drugs are not metabolized by the liver, but multidrug and toxin extrusion protein 1 (MATE1) expressed in hepatocytes is involved in the clearance of drugs, which is transported to the kidney through bile or through blood (Gong et al, 2012).…”

Section: The Main Process Of Metformin In the Human Bodymentioning

confidence: 99%

Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota

Wang,

Jia,

Cong

2024

Front. Microbiol.

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Metformin is of great focus because of its high safety, low side effects, and various effects other than lowering blood sugar, such as anti-inflammation, anti-tumor, and anti-aging. Studies have shown that metformin has a modulating effect on the composition and function of the intestinal microbiota other than acting on the liver. However, the composition of microbiota is complex and varies to some extent between species and individuals, and the experimental design of each study is also different. Multiple factors present a major obstacle to better comprehending the effects of metformin on the gut microbiota. This paper reviews the regulatory effects of metformin on the gut microbiota, such as increasing the abundance of genus Akkermansia, enriching short-chain fatty acids (SCFAs)-producing bacterial genus, and regulating gene expression of certain genera. The intestinal microbiota is a large and vital ecosystem in the human body and is considered to be the equivalent of an “organ” of the human body, which is highly relevant to human health and disease status. There are a lot of evidences that the gut microbiota is responsible for metformin’s widespread effects. However, there are only a few systematic studies on this mechanism, and the specific mechanism is still unclear. This paper aims to summarize the possible mechanism of metformin in relation to gut microbiota.

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“…OCT1 and OCT3 both take metformin from the bloodstream and store it in hepatocytes (27,28). Polyspecificity is one of the OCT1's most distinguishing characteristics (29). Currently, it has been determined that 150 cationic organic molecules of various chemical compositions, including well used medications like metformin, are substrates for the OCT1 (30)(31)(32).…”

Section: Metformin Transporters Involved In Its Pharmacokineticsmentioning

confidence: 99%

A Review of the Impact of Pharmacogenetics and Metabolomics on the Efficacy of Metformin in Type 2 Diabetes

Damanhouri¹,

Alkreathy²,

Alharbi³

et al. 2023

Int. J. Med. Sci.

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Metformin is the most often prescribed drug for people with type 2 diabetes (T2D). More than 120 million patients with T2D use metformin worldwide. However, monotherapy fails to achieve glycemic control in a third of the treated patients. Genetics contribute to some of the inter-individual variations in glycemic response to metformin. Numerous pharmacogenetic studies have demonstrated that variations in genes related to pharmacokinetics and pharmacodynamics of metformin's encoding transporters are mainly associated with metformin response. The goal of this review is to evaluate the current state of metformin pharmacogenetics and metabolomics research, discuss the clinical and scientific issues that need to be resolved in order to increase our knowledge of patient response variability to metformin, and how to improve patient outcomes. Metformin's hydrophilic nature and absorption as well as its action mechanism and effectiveness on T2D initiation are discussed. The impacts of variations associated with various genes are analysed to identify and evaluate the effect of genetic polymorphisms on the therapeutic activity of metformin. The metabolic pattern of T2D and metformin is also indicated. This is to emphasise that studies of pharmacogenetics and metabolomics could expand our knowledge of metformin response in T2D.

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OCT1 Polyspecificity—Friend or Foe?

Cited by 9 publications

References 51 publications

Stereoselectivity in Cell Uptake by SLC22 Organic Cation Transporters 1, 2, and 3

Stereoselectivity in Cell Uptake by SLC22 Organic Cation Transporters 1, 2, and 3

Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota

A Review of the Impact of Pharmacogenetics and Metabolomics on the Efficacy of Metformin in Type 2 Diabetes

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