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Polymorphism of Organic Cation Transporter 2 Improves Glucose-Lowering Effect of Metformin via Influencing Its Pharmacokinetics in Chinese Type 2 Diabetic Patients

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Abstract

Background and Objectives

This study aimed to investigate how the organic cation transporter 2 nucleotide polymorphism at site 808 (G → T) affects metformin pharmacokinetics and its long-term anti-diabetic effect.

Methods

A total of 220 newly diagnosed type 2 diabetes patients taking oral metformin were recruited, genotyped and then divided into three groups by SLC22A2 genotypes (G/G, G/T, T/T). Nine patients in the GG genotype group, five patients in the GT genotype group and four patients in the TT genotype group were randomly selected for the metformin pharmacokinetic study. A randomized cohort study with 1-year follow-up was performed to clarify the metformin pharmacodynamics.

Results

After 1 year, the decrease in glycosylated hemoglobin (HbA1c) levels in subjects with the heterozygous variant genotype (GT) was significantly greater than in those with the wild-type homozygote (−2.2 % in GT vs. −1.1 % in GG, P < 0.05) after adjustment for baseline HbA1c levels, exercise and diet in each group. There were also differences in the pharmacokinetic parameters (95 % confidence interval) of metformin between these two groups [area under the concentration–time curve (AUC)0–∞ 19.7 (15.7–23.8) vs. 14.3 (11.7–16.9) μg h/L; renal clearance (CLr) 16.8 (8.5–25.0) vs. 34.1 (24.9–43.2) L/h; tubular secretion clearance (CLt) 8.1 (2.2–18.1) vs. 22.7 (15.5–29.8) L/h; all P < 0.05]. Multivariate analysis further revealed that the presence of T alleles and gender were independent influencing factors of urine excretion of metformin (P < 0.05).

Conclusion

As well as gender, the glucose-lowering efficiency of metformin can be enhanced by SLC22A2 808G > T variants through the delay of its transportation and CLr in Chinese type 2 diabetes populations.

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Acknowledgments

This study was supported by the National Natural Science Fund of China (Grant Nos. 81070650 and 81270397 for Fang Liu).

Conflict of interest

The authors declare that there are no conflict of interests regarding the publication of this paper.

Authors’ contributions

Wolin Hou and Dandan Zhang analyzed the data and wrote the manuscript. Fang Liu and Weiping Jia designed the study and revised the manuscript. Dandan Zhang, Yuqian Bao and Wei Lu performed the pharmacokinetic study of metformin. Qing Li and Taishan Zheng performed the genotype research, and Lili Wan contributed to metformin concentration determination.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai Clinical Medical Center of Diabetes, Shanghai Key Clinical Center of Metabolic Diseases, Shanghai Institute for Diabetes, Shanghai Key Laboratory of Diabetes, Shanghai, 200233, People’s Republic of China

    Wolin Hou, Dandan Zhang, Wei Lu, Taishan Zheng, Qing Li, Yuqian Bao, Fang Liu & Weiping Jia

  2. Department of Pharmacy, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China

    Lili Wan

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  1. Wolin Hou
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  2. Dandan Zhang
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  5. Lili Wan
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  6. Qing Li
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  8. Fang Liu
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  9. Weiping Jia
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Correspondence to Fang Liu.

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Hou, W., Zhang, D., Lu, W. et al. Polymorphism of Organic Cation Transporter 2 Improves Glucose-Lowering Effect of Metformin via Influencing Its Pharmacokinetics in Chinese Type 2 Diabetic Patients. Mol Diagn Ther 19, 25–33 (2015). https://doi.org/10.1007/s40291-014-0126-z

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  • DOI: https://doi.org/10.1007/s40291-014-0126-z

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