Variation in the Plasma Membrane Monoamine Transporter (PMAT) (Encoded by <i>SLC29A4</i>) and Organic Cation Transporter 1 (OCT1) (Encoded by <i>SLC22A1</i>) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: An IMI DIRECT Study

Dawed, Adem Y; Zhou, Kaixin; Leeuwen, Nienke van; Robertson, Neil; Koivula, Robert W.; Elders, Petra; Rauh, Simone P.; Jones, Angus G.; Holl, Reinhard W.; Stingl, Julia; Franks, Paul W.; McCarthy, Mark; Hart, Leen M ’t; Pearson, Ewan R.

doi:10.2337/dc18-2182

Cited by 46 publications

(24 citation statements)

References 51 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Eighteen articles comprised of 10, 383 subjects were included in this review ( Table 2 ). Among these, two studies were multinational (Bailey et al, 2010 ; Dawed et al, 2019 ). While 12 studies were conducted in Europe (Holstein et al, 2005 , 2011 , 2012 ; Ragia et al, 2009 , 2012 , 2014 ; Tarasova et al, 2012 ; Dujic et al, 2015 , 2016a , b , 2018 ; Dawed et al, 2016 ), three were in Asia (Kahn et al, 2006 ; Sato et al, 2010 ; Gökalp et al, 2011 ) and one was in the US (Ruaño et al, 2009 ).…”

Section: Resultsmentioning

confidence: 99%

“…Five of these studies comprising of 5,438 subjects were conducted to investigate association between genetic polymorphisms and metformin-related GI adverse effects (Tarasova et al, 2012 ; Dujic et al, 2015 , 2016a , b ; Dawed et al, 2019 ). Association between genetic polymorphisms and the risks of sulfonylurea-induced hypoglycemia was evaluated in nine studies comprising of 1,944 subjects (Holstein et al, 2005 , 2011 , 2012 ; Ragia et al, 2009 , 2012 , 2014 ; Sato et al, 2010 ; Gökalp et al, 2011 ; Dujic et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

“…While 12 studies were conducted in Europe (Holstein et al, 2005(Holstein et al, , 2011Ragia et al, 2009Ragia et al, , 2012Ragia et al, , 2014Tarasova et al, 2012;Dujic et al, 2015Dujic et al, , 2016aDujic et al, ,b, 2018Dawed et al, 2016), three were in Asia ( Kahn et al, 2006;Sato et al, 2010;Gökalp et al, 2011) and one was in the US (Ruaño et al, 2009). Five of these studies comprising of 5,438 subjects were conducted to investigate association between genetic polymorphisms and metformin-related GI adverse effects (Tarasova et al, 2012;Dujic et al, 2015Dujic et al, , 2016aDawed et al, 2019). Association between genetic polymorphisms and the risks of sulfonylurea-induced hypoglycemia was evaluated in nine studies comprising of 1,944 subjects (Holstein et al, 2005(Holstein et al, , 2011Ragia et al, 2009Ragia et al, , 2012Ragia et al, , 2014Sato et al, 2010;Gökalp et al, 2011;Dujic et al, 2018).…”

Section: Characteristics Of Included Studiesmentioning

confidence: 99%

See 2 more Smart Citations

The Genetics of Adverse Drug Outcomes in Type 2 Diabetes: A Systematic Review

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background: Adverse drug reactions (ADR) are a major clinical problem accounting for significant hospital admission rates, morbidity, mortality, and health care costs. One-third of people with diabetes experience at least one ADR. However, there is notable interindividual heterogeneity resulting in patient harm and unnecessary medical costs. Genomics is at the forefront of research to understand interindividual variability, and there are many genotype-drug response associations in diabetes with inconsistent findings. Here, we conducted a systematic review to comprehensively examine and synthesize the effect of genetic polymorphisms on the incidence of ADRs of oral glucose-lowering drugs in people with type 2 diabetes.Methods: A literature search was made to identify articles that included specific results of research on genetic polymorphism and adverse effects associated with oral glucose-lowering drugs. The electronic search was carried out on 3rd October 2020, through Cochrane Library, PubMed, and Web of Science using keywords and MeSH terms.Result: Eighteen articles consisting of 10, 383 subjects were included in this review. Carriers of reduced-function alleles of organic cation transporter 1 (OCT 1, encoded by SLC22A1) or reduced expression alleles of plasma membrane monoamine transporter (PMAT, encoded by SLC29A4) or serotonin transporter (SERT, encoded by SLC6A4) were associated with increased incidence of metformin-related gastrointestinal (GI) adverse effects. These effects were shown to exacerbate by concomitant treatment with gut transporter inhibiting drugs. The CYP2C9 alleles, *2 (rs1799853C>T) and *3 (rs1057910A>C) that are predictive of low enzyme activity were more common in subjects who experienced hypoglycemia after treatment with sulfonylureas. However, there was no significant association between sulfonylurea-related hypoglycemia and genetic variants in the ATP-binding cassette transporter sub-family C member 8 (ABCC8)/Potassium Inwardly Rectifying Channel Subfamily J Member 11 (KCNJ11). Compared to the wild type, the low enzyme activity C allele at CYP2C8*3 (rs1057910A>C) was associated with less weight gain whereas the C allele at rs6123045 in the NFATC2 gene was significantly associated with edema from rosiglitazone treatment.Conclusion: In spite of limited studies investigating genetics and ADR in diabetes, some convincing results are emerging. Genetic variants in genes encoding drug transporters and metabolizing enzymes are implicated in metformin-related GI adverse effects, and sulfonylurea-induced hypoglycemia, respectively. Further studies to investigate newer antidiabetic drugs such as DPP-4i, GLP-1RA, and SGLT2i are warranted. In addition, pharmacogenetic studies that account for race and ethnic differences are required.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Characteristics Of Included Studiesmentioning

confidence: 99%

See 1 more Smart Citation

The Genetics of Adverse Drug Outcomes in Type 2 Diabetes: A Systematic Review

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…These observations, coupled with no change in half‐life, suggested that goldenseal decreased metformin oral bioavailability by altering intestinal permeability, transport, and/or other processes involved in metformin absorption. Multiple uptake transporters contribute to the intestinal absorption of metformin, including OCT1/3, ThTR‐2, PMAT, and SERT ( Figure ) 37–39 . OCT3, ThTR‐2, PMAT, and SERT are expressed on the luminal membrane, whereas the reported localization of OCT1 is conflicting 40–42 .…”

Section: Discussionmentioning

confidence: 99%

“…Proposed transporter‐mediated mechanism underlying the decreased metformin systemic exposure upon goldenseal exposure. The indicated transporters have been reported to facilitate intestinal absorption of metformin 37–42 . Arrows represent uptake or efflux; double‐headed arrows represent bidirectional transport.…”

Section: Discussionmentioning

confidence: 99%

Assessing Transporter‐Mediated Natural Product‐Drug Interactions Via In vitro‐In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail

Nguyen

Tian

Tanna

et al. 2020

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

The botanical natural product goldenseal can precipitate clinical drug interactions by inhibiting cytochrome P450 (CYP) 3A and CYP2D6. Besides P‐glycoprotein, effects of goldenseal on other clinically relevant transporters remain unknown. Established transporter‐expressing cell systems were used to determine the inhibitory effects of a goldenseal extract, standardized to the major alkaloid berberine, on transporter activity. Using recommended basic models, the extract was predicted to inhibit the efflux transporter BCRP and uptake transporters OATP1B1/3. Using a cocktail approach, effects of the goldenseal product on BCRP, OATP1B1/3, OATs, OCTs, MATEs, and CYP3A were next evaluated in 16 healthy volunteers. As expected, goldenseal increased the area under the plasma concentration‐time curve (AUC0–inf) of midazolam (CYP3A; positive control), with a geometric mean ratio (GMR) (90% confidence interval (CI)) of 1.43 (1.35–1.53). However, goldenseal had no effects on the pharmacokinetics of rosuvastatin (BCRP and OATP1B1/3) and furosemide (OAT1/3); decreased metformin (OCT1/2, MATE1/2‐K) AUC0–inf (GMR, 0.77 (0.71–0.83)); and had no effect on metformin half‐life and renal clearance. Results indicated that goldenseal altered intestinal permeability, transport, and/or other processes involved in metformin absorption, which may have unfavorable effects on glucose control. Inconsistencies between model predictions and pharmacokinetic outcomes prompt further refinement of current basic models to include differential transporter expression in relevant organs and intestinal degradation/metabolism of the precipitant(s). Such refinement should improve in vitro‐in vivo prediction accuracy, contributing to a standard approach for studying transporter‐mediated natural product‐drug interactions.

show abstract