of the endogenous biomarkers NMN and N1‐methyladenosine for MATE drug interaction assessments in healthy volunteers.
3.7 PHARMACOGENETICS
The impact of genetic variation in SLC47A1 and SLC47A2 can impact both pharmacokinetics and pharmacodynamics.
3.7.1 Metformin Pharmacokinetics
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.
3.7.2 Metformin Efficacy
3.7.2.1 Diabetes
The first large study to report an association between SLC47A1 polymorphisms and changes in glucose control, as noted by hemoglobin A1c, in diabetics treated with metformin was informed from the European Rotterdam Study (n = 116) [108]. The rs2289669 G > A polymorphism was significantly associated with metformin response. For each minor A allele, hemoglobin A1c reduction was 0.3% greater. Subsequently, relationships between OCT1 (SLC22A1; rs622342 A > C) and SLC47A1 (rs2289669; G > A) polymorphisms and effects on glucose lowering were investigated by the Rotterdam investigators [109]. The study used multiplicative interaction analyses to evaluate changes in HbA1c in patients newly prescribed metformin (n = 98). The decrease in hemoglobin A1c levels was greatest for each SLC22A1 A allele (wild type) and SLC47A1 A allele (variant). This study demonstrated the interaction between polymorphisms in two transporter genes in determining efficacy of treatment with metformin. Despite these findings associating glycemic control with polymorphisms in MATE and OCT2 transport genes in patients undergoing therapy with metformin, a large meta‐analysis in Europeans failed to detect these associations in 7,968 subjects in the Metformin Genetics Consortium (MetGen) [110].
Two studies by separate investigators evaluated associations between human genetic variants in SLC47A1 and SLC47A2 and MATE1/MATE2/2‐K transport function [111, 112]. Subsequently, the influence of promoter variants in SLC47A1 (−66 T > C, rs2252281) and SLC47A2 (−130 G > A, rs12943590) on metformin disposition and response was reported [113]. Healthy volunteers (n = 57) receiving metformin exhibited increased renal and secretory clearances if they were carriers of the variant SLC47A2 and wild‐type
