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The following section highlights the studies that have supported the associations of genetic polymorphisms in SLC47A1/MATE1 and SLC47A2/MATE2 with the clearance of metformin. Table 3.5 provides an overview of key polymorphisms and their functional impact on transport (when applicable).

Another early study sought to evaluate associations between MATE2‐K genetic variants in coding and noncoding regions and metformin pharmacokinetics in healthy Korean subjects (n = 45) [106]. The study also examined the function of common haplotypes in the promoter region using in vitro luciferase assays. Two SLC47A2 promoter genetic variants (−130 G > A) and a haplotype containing two polymorphisms (−609 G > A and −396 G > A) showed a significant increase in an in vitro reporter activity assay. Healthy volunteers homozygous for either the variant or haplotype exhibited increased metformin renal clearance and secretion compared with the reference group. The authors concluded that promoter variants and haplotypes in SLC47A2 are associated with renal clearance of metformin.

TABLE 3.5 Human genetic variation in SLC47A1 and SLC47A2

Transporter	dbSNPa	Base changeb	Amino acid change
SLC47A1/ MATE1	rs72466470	−32 G > A	N.A.
rs2252281	−66 T > C	N.A.
rs111060521	28 G > T	V10L
rs77630697	191 G > A	G64D
rs77474263	373 C > T	L125F
rs35646404	404 T > C	T159M
rs2289669	816 G > A
rs111060526	929 C > T	A310V
rs111060527	983 A > C	D328A
rs35790011	1,012 G > A	V338I
rs111060528	1,421 A > G	N474S
rs76645859	1,438 G > A	V480M
rs35395280	1,490 G > C or G > T	C497S
rs78700676	1,557 G > C	Q519H
SLC47A2/ MATE2‐K	rs12943590	−130 G > A	N.A.
rs111060529	192 G > T	K64N
rs111060532	632–633 GC > TT	G211V

^a All information from dbSNP or references (112, 134, 135).

^b Relative to the coding DNA sequence position.

N.A.: not applicable.

MATE function can be impacted by the combined effect of a MATE inhibitor and loss‐of‐function variants. The influence of multiple polymorphisms on metformin clearance was found to be dependent on the combinations evaluated when the MATE inhibitor trimethoprim was administered [107]. In a study conducted in healthy volunteers (n = 24) administered metformin and trimethoprim, metformin total clearance and renal clearance were reduced and half‐life increased in the presence versus absence of trimethoprim. The Cmax and exposures were also increased. The study reported a reduction in the clearance of the endogenous biomarker creatinine with trimethoprim administration. When the study was analyzed according to SLC22A2 (rs316019) and SLC47A1 (rs2289669) genotype groups (in combination), individuals with the polymorphic genotypes for both transporters failed to have demonstrated differences in metformin pharmacokinetics in the presence or absence of trimethoprim. However, the presence of either polymorphic SLC47A1 with wild‐type SLC22A2 or wild‐type SLC47A1 with polymorphic SLC22A2 exhibited increased metformin Cmax and exposures in the presence of trimethoprim. Hence, the combination of transporter genetics may result in observed differences with potent MATE inhibitors.