Genetic polymorphisms of organic cation transporters 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes mellitus: a systematic review protocol

Mato, E.P. Mofo; Guewo-Fokeng, Magellan; Essop, M. Faadiel; Owira, Peter M. O.

doi:10.1186/s13643-018-0773-y

Cited by 8 publications

(6 citation statements)

References 43 publications

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“…In contrast to these findings, the concomitant administration of GRT with metformin in vivo did not affect the plasma concentration of metformin, suggesting that interaction of GRT (rooibos) with metformin is unlikely. Although metformin is not dependent on cytochrome P450 (CYP450) metabolism, drug transporting membrane proteins, such as the solute carrier family of transporters, including organic cation transporters (OCTs), and ATP-binding cassette transporters alters the extent of its pharmacological effects (Mato et al, 2018; Wu et al, 2018). GRT alone significantly increased Abcc2 mRNA expression, while in combination with metformin or atorvastatin, no significant effect was demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interaction of Green Rooibos Extract With Atorvastatin and Metformin in Rats

et al. 2019

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An aspalathin-rich green rooibos extract (Afriplex GRT™) has demonstrated anti-diabetic and hypolipidemic properties, while also moderately inhibiting CYP3A4 activity, suggesting a potential for herb–drug interaction. The present study, therefore, evaluated the effects of orally administered GRT on the pharmacokinetics of atorvastatin and metformin in Wistar rats. Wistar rats were orally treated with GRT (50 mg/kg BW), atorvastatin (40 mg/kg BW) or metformin (150 mg/kg BW) alone or 50 mg/kg BW GRT in combination with 40 mg/kg BW atorvastatin or 150 mg/kg BW metformin. Blood samples were collected at 0, 10, and 30 min and 1, 2, 4, 6, and 8 h and plasma samples obtained for Liquid chromatography-mass spectrometry (LC-MS/MS) analyses. Non-compartment and two-compartment pharmacokinetic parameters of atorvastatin and metformin in the presence or absence of GRT were determined by PKSolver version 2.0 software. Membrane transporter proteins, ATP-binding cassette sub-family C member 2 (Abcc2), solute carrier organic anion transporter family, member 1b2 (Slco1b2), ATP-binding cassette, sub-family B (MDR/TAP), member 1A (Abcb1a), and organic cation transporter 1 (Oct1) mRNA expression were determined using real-time PCR expression data normalized to β-actin and hypoxanthine-guanine phosphoribosyltransferase (HPRT), respectively. Co-administration of GRT with atorvastatin substantially increased the maximum plasma concentration (Cmax) and area of the plasma concentration–time curve (AUC0-8) of atorvastatin by 5.8-fold (p = 0.03) and 5.9-fold (p = 0.02), respectively. GRT had no effect on the plasma levels of metformin. GRT increased Abcc2 expression and metformin downregulated Abcb1a expression while the combination of GRT with atorvastatin or metformin did not significantly alter the expression of Slco1b1 or Oct1 did not significantly alter the expression of Sclo1b2 or Oct1. Co-administration of GRT with atorvastatin in rats may lead to higher plasma concentrations and, therefore, to an increase of the exposure to atorvastatin.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interaction of Green Rooibos Extract With Atorvastatin and Metformin in Rats

et al. 2019

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“…Recently, OCT1 has been implicated in the transport of LTG both into hepatocytes and at the blood–brain barrier (Dickens et al, 2012). The genetic effects of OCT1 polymorphisms on responses and adverse events have been found to be ambiguous and to potentially be population-specific (Mato et al, 2018). Among the known polymorphisms of the SLC22A1 gene, SLC22A1 rs628031 is among the most studied.…”

Section: Introductionmentioning

confidence: 99%

Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy

et al. 2019

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Lamotrigine (LTG) is a second-generation anti-epileptic drug widely used for focal and generalized seizures in adults and children, and as a first-line medication in pregnant women and women of childbearing age. However, LTG pharmacokinetics shows high inter-individual variability, thus potentially leading to therapeutic failure or side effects in patients. This prospective study aimed to establish a population pharmacokinetics model for LTG in Chinese patients with epilepsy and to investigate the effects of genetic variants in uridine diphosphate glucuronosyltransferase (UGT) 1A4, UGT2B7, MDR1, ABCG2, ABCC2, and SLC22A1, as well as non-genetic factors, on LTG pharmacokinetics. The study population consisted of 89 patients with epilepsy, with 419 concentrations of LTG. A nonlinear mixed effects model was implemented in NONMEM software. A one-compartment model with first-order input and first-order elimination was found to adequately characterize LTG concentration. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. The use of valproic acid decreased CL/F by 38.5%, whereas the co-administration of rifampicin caused an increase in CL/F of 64.7%. The CL/F decreased by 52.5% in SLC22A1 -1222AA carriers. Patients with the ABCG2 -34AA genotype had a 42.0% decrease in V/F, whereas patients with the MDR1 -2677TT and C3435TT genotypes had a 136% increase in V/F. No obvious genetic effect of UGT enzymes was found relative to the concentrations of LTG in Chinese patients. Recommended dose regimens for patients with different gene polymorphisms and comedications were estimated on the basis of Monte Carlo simulations and the established model. These findings should be valuable for developing individualized dosage regimens in adult and adolescent Chinese patients 13–65 years of age.

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“…Metformin is mostly the rst line of treatment and most commonly used drugs for T2DM. However, T2DM patients show considerable interindividual variations in metformin response, with approximately 35-40% of patients taking this drug fail to achieve initial glycemic control [10]. The phenotypic differences in drug disposition and action could result from polymorphisms in genes that regulate pharmacokinetics/pharmacodynamics of metformin.…”

Section: Discussionmentioning

confidence: 99%

Association of Single Nucleotide Polymorphism in OCT1 and OCT3 Genes with the Efficacy of Metformin Response in North Indian Type 2 Diabetes Mellitus Patients.

Rizvi,

Raza,

Mahdi

2023

Preprint

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Purpose Interindividual variation in efficacy of metformin among type 2 diabetes mellitus (T2DM) patients have been associated with several genetic variants. Understanding the genetic pathways involved in pharmacodynamics of metformin can affect personalized treatment of T2DM. Our study aimed to find the implication of genetic polymorphism in organic cation transporters (OCT1 and OCT3) genes on drug efficacy of metformin therapy in T2DM patients from North India. Methods This study evaluated the role of OCT1 (rs628031) and OCT3 (rs2292334) polymorphism in metformin response on T2DM patients. Response to metformin was defined by HbA1c levels based on which patients (n = 177) were divided into two groups: responders (HbA1C < 7% ; n = 127) and non-responders (HbA1C ≥ 7%; n = 50). The responders were further subcategorized as T2DM patients on monotherapy (n = 55) and on combination therapy (n = 72). Genotyping was done using PCR-RFLP approach. Results No significant association was found between OCT1 (rs628031) polymorphism and metformin response in T2DM patients. On the other hand, significant association of OCT3 (rs rs2292334) polymorphism was observed with metformin response where AA genotype carriers showed higher efficacy of metformin both in mono [OR (CI) = 0.29(0.11–0.72) and p = 0.007] and combination therapy [OR (CI) = 0.41(0.16-1.0) and p = 0.047]. Also, A allele was more prevalent in responders [OR (CI) = 0.48(0.28–0.84) and p = 0.010] while G allele was found to be associated with inefficacy of metformin in T2DM patients [OR (CI) = 2.07(1.19–3.61) and p = 0.010]. Conclusion Genotyping of OCT3 (rs2292334) might be useful in predicting the response to metformin in T2DM patients.

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Genetic polymorphisms of organic cation transporters 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes mellitus: a systematic review protocol

Cited by 8 publications

References 43 publications

Pharmacokinetic Interaction of Green Rooibos Extract With Atorvastatin and Metformin in Rats

Pharmacokinetic Interaction of Green Rooibos Extract With Atorvastatin and Metformin in Rats

Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy

Association of Single Nucleotide Polymorphism in OCT1 and OCT3 Genes with the Efficacy of Metformin Response in North Indian Type 2 Diabetes Mellitus Patients.

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