OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine

Wang, Zhijun; Yin, Ophelia; Tomlinson, Brian; Chow, Moses S. S.

doi:10.1097/fpc.0b013e328302cd41

Cited by 246 publications

(196 citation statements)

References 30 publications

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“…This analysis showed that there were three genotypes (GG, GT, and TT) at position 808 in the SLC22A2 gene in Chinese Hans with T2DM. The genotype in the two groups and the total group were in accordance with Hardy-Weinberg equilibrium, and the T allele frequency was 12.9%, which was similar to the data in healthy populations from Hong Kong (13.3%), Japan (16.8%), and Korea (11%) [13,20,21] . This research further investigated the relationship between the SLC22A2 808G>T polymorphism and plasma lactate levels in these T2DM patients treated with or without metformin.…”

Section: Discussionsupporting

confidence: 70%

“…The non-synonymous SNP, 808G>T (Ala270Ser), was found to be present in 13.3% of individuals from a healthy population of Chinese from Hong Kong. Subjects who are homozygous for 808G>T tend to have higher plasma exposure to metformin, and this can be further enhanced in elderly patients or those with renal dysfunction [13] ; however, other variations in the OCT2 gene were rare (less than 3%) in the Chinese population. Thus, the variant that is the most likely to be related to metformin sensitivity and plasma lactate in Chinese Hans with T2DM may be the 808G/ T transversion in the SLC22A2 gene.…”

Section: Introductionmentioning

confidence: 99%

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SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin

Liu

Zheng

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate the potential relationship between the SLC22A2 gene polymorphism and blood lactate concentration in Shanghai Hans suffering from type 2 diabetes mellitus (T2DM). Methods: The SLC22A2 single nucleotide polymorphism (SNP) 808G/T was genotyped in 400 T2DM patients, including a metformintreated group (n=200) and a non-metformin-treated group (n=200). Fasting plasma lactic acid levels were measured with an enzymeelectrode assay. Biochemical indexes, including plasma alanine aminotransferase (ALT), creatinine (Cr), and glycolated hemoglobin (HbA1c), were also measured. Results: The fasting plasma lactate concentration in the metformin-treated group was significantly higher than that in the non-metformin-treated group (1.29±0.45 mmol/L vs 1.18±0.44 mmol/L, P=0.015). Additionally, the ratio of patients with hyperlactacidemia was 8% (16/200) for the metformin-treated group and 5.5% (11/200) for the non-metformin-treated group, with no lactic acidosis found in either group. The frequency of the SLC22A2 808G/T T allele was 12.9%. Patients with the mutant genotype (TT) had a higher blood lactate concentration in the metformin-treated group than those in the non-metformin-treated group (t=2.492, P=0.013). This trend was not observed in the GG and GT genotypes when compared with metformin-treated and non-metformin-treated groups. Patients with the mutant genotype (TT) in the metformin-treated group also had a higher incidence of hyperlactacidemia compared with the GG genotype (40.0% vs 6.9%, P=0.050) in the metformin-treated group and the GG (6.0%, P=0.042) or GT (4.3%, P=0.043) genotypes in the non-metformin-treated group. In the metformin-treated group, there were significant gender differences in lactate concentrations in the TT (2.18±0.15 vs 1.04±0.27 mmol/L, P=0.008) and GG genotypes (1.40±0.51 vs 1.19±0.35 mmol/L, P=0.004). The lactate levels of women with the TT genotype were the highest in the metformin-treated group, but differences in lactate levels among the genotypes were not observed in the non-metformin-treated group. Conclusion: There is an 808G/T polymorphism in the SLC22A2 gene in Chinese Hans with T2DM. The 808G>T variance in the SLC22A2 gene can affect the plasma lactate level and the incidence of hyperlactacidemia in T2DM patients undergoing metformin therapy. Additionally, the female patients carrying the TT genotype are prone to lactatemia.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin

Liu

Zheng

et al. 2010

Acta Pharmacol Sin

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“…The current research regarding the SNP rs316019 (808 G>T) in the gene encoding OCT2 is conflicting, but it does appear to affect the renal clearance (CLR) of metformin [28,29]. To avoid known and unknown effects of genetic variations, 20 men who were all wild-type for known reduced function SNPs in OCT1 (rs12208357, rs34130495, rs72552763, rs34059508) and OCT2 (rs316019) were included in this study.…”

Section: Study Participantsmentioning

confidence: 99%

Intake of St John's wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone

Stage

Pedersen

Damkier

et al. 2015

Brit J Clinical Pharma

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AIMSOur objective was to investigate the steady-state pharmacokinetic and pharmacodynamic interaction between the antidepressive herbal medicine St John's wort and the antidiabetic drug metformin. METHODSWe performed an open cross-over study in 20 healthy male subjects, who received 1 g of metformin twice daily for 1 week with and without 21 days of preceding and concomitant treatment with St John's wort. The pharmacokinetics of metformin was determined, and a 2 h oral glucose tolerance test was performed. RESULTSSt John's wort decreased the renal clearance of metformin but did not affect any other metformin pharmacokinetic parameter. The addition of St John's wort decreased the area under the glucose concentration-time curve [702 (95% confidence interval, 643-761) vs. 629 min*mmol/L (95% confidence interval, 568-690), P = 0.003], and this effect was caused by a statistically significant increase in the acute insulin response. CONCLUSIONSSt John's wort improves glucose tolerance by enhancing insulin secretion independently of insulin sensitivity in healthy male subjects taking metformin. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?• The pregnane X receptor agonist rifampicin lowers the plasma concentration of metformin and increases the glucose tolerance in healthy individuals.• It has not previously been investigated whether the herbal medicine St John's wort (SJW), which is also an agonist of the pregnane X receptor, exerts the same effect. WHAT THIS STUDY ADDS• There was no difference in the pharmacokinetics of metformin, except for a small albeit statistically significant reduction in renal clearance after treatment with SJW.• We show that SJW increases glucose tolerance in healthy subjects who ingest metformin.• The effect was caused by an increase in the acute insulin response.

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“…Homozygous carriers of the low activity SLC22A2 variant, 270S, were reported to have significantly lower rates of renal clearance and higher plasma concentration of metformin than those homozygous for the active variant, 270A. 11,29 On the other hand, low-function SLC22A1 variants including R61C, G401S and G465R have been associated with significantly higher rates of renal clearance of metformin. 30 In addition to the effect on metformin pharmacokinetics, low-function SLC22A1 variants have been also associated with significantly decreased glucose-lowering response of metformin.…”

Section: Resultsmentioning

confidence: 99%

Screening of genetic variations of SLC15A2, SLC22A1, SLC22A2 and SLC22A6 genes

Cheong

Kim

et al. 2011

J Hum Genet

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A growing list of membrane-spanning proteins involved in the transport of a large variety of drugs has been recognized and characterized to include peptide and organic anion/cation transporters. Given such an important role of transporter genes in drug disposition process, the role of single-nucleotide polymorphisms (SNPs) in such transporters as potential determinants of interindividual variability in drug disposition and pharmacological response has been investigated. To define the distribution of transporter gene SNPs across ethnic groups, we screened 450 DNAs in cohorts of 250 Korean, 50 Han Chinese, 50 Japanese, 50 African-American and 50 European-American ancestries for 64 SNPs in four transporter genes encoding proteins of the solute carrier family (SLC15A2, SLC22A1, SLC22A2 and SLC22A6). Of the 64 SNPs, 19 were core pharmacogenetic variants and 45 were HapMap tagging SNPs. Polymorphisms were genotyped using the golden gate genotyping assay. After genetic variability, haplotype structures and ethnic diversity were analyzed, we observed that the distributions of SNPs in a Korean population were similar to other Asian groups (Chinese and Japanese), and significantly different from African-American and European-American cohorts. Findings from this study would be valuable for further researches, including pharmacogenetic studies for drug responses.

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OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine

Cited by 246 publications

References 30 publications

SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin

SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin

Intake of St John's wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone

Screening of genetic variations of SLC15A2, SLC22A1, SLC22A2 and SLC22A6 genes

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