Transl Clin Pharmacol.  2018 Jun;26(2):79-85. 10.12793/tcp.2018.26.2.79.

Effect of plasma membrane monoamine transporter genetic variants on pharmacokinetics of metformin in humans

• Moon SJ
• Oh J
• Lee SH
• Choi Y
• Yu KS
• Chung JY

• KMID: 2413831
• DOI: http://doi.org/10.12793/tcp.2018.26.2.79

Abstract

Metformin, an oral hypoglycemic agent belonging to biguanide class, is widely used to treat type 2 diabetes mellitus, and several drug transporters such as organic cation transporters (OCTs), multidrug and toxin extrusion transporter (MATE), and plasma membrane monoamine transporter (PMAT) are thought to affect its disposition. We evaluated the role of PMAT genetic variations on the pharmacokinetic characteristics of metformin in a Korean population. In this retrospective study, 91 healthy subjects from four different metformin pharmacokinetic studies were analyzed; in each study, the subjects were administered two oral doses of metformin at intervals of 12 hours and dose-normalized pharmacokinetic parameters were compared between the subjects' genotypes. Subjects who had more than one allele of c.883-144A>G single nucleotide polymorphism (SNP) in PMAT gene (rs3889348) showed increased renal clearance of metformin compared to wild-type subjects (814.79 ± 391.73 vs. 619.90 ± 195.43 mL/min, p=0.003), whereas no differences in metformin exposure were observed between the PMAT variant subjects and wild-type subjects. Similarly, subjects with variant rs316019 SNP in OCT2 showed decreased renal clearance of metformin compared to wild-type subjects (586.01 ± 160.54 vs. 699.13 ± 291.40 mL/min, p=0.048). Other SNPs in PMAT and MATE1/2-K genes did not significantly affect metformin pharmacokinetics. In conclusion, the genetic variation of c.883-144A>G SNP in PMAT significantly affects the renal clearance of metformin in healthy Korean male subjects.

Keyword

Metformin; Plasma membrane monoamine transporter; Pharmacokinetics

MeSH Terms

Alleles
Cell Membrane*
Diabetes Mellitus, Type 2
Genetic Variation
Genotype
Healthy Volunteers
Humans*
Male
Metformin*
Pharmacokinetics*
Plasma*
Polymorphism, Single Nucleotide
Retrospective Studies
Metformin

Figure

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  Figure 1 Effect of 5 SNPS in PMAT on renal clearance of metformin. A) PMAT SNP rs2685753, B) PMAT SNP rs3889348, C) PMAT SNP rs4720572, D) PMAT SNP rs4299914, E) PMAT SNP rs6971788.

• 

  Figure 2 Effect of 5 SNPS in PMAT on dose-normalized AUC0-last of metformin. A) PMAT SNP rs2685753, B) PMAT SNP rs3889348, C) PMAT SNP rs4720572, D) PMAT SNP rs4299914, E) PMAT SNP rs6971788.

• 

  Figure 3 Effect of OCT2 SNP rs316019 on A) dose-normalized AUC0-last of metformin and B) renal clearance of metformin.

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