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Drug Transporters


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transport of NMN in vitro and in healthy volunteers (n = 8) [102]. Inhibition constants for pyrimethamine were 83 nmol/l for MATE1 and 56 nmol/l for MATE2‐K. Total Cmax of pyrimethamine after 50 mg was expected to be 8.3 μM (unbound Cmax 7.22 μM). Cmax/IC50 quotients predicted in vivo interactions with MATE1 and MATE2‐K, which was confirmed as the renal clearance of NMN was reduced in the presence of pyrimethamine. The study demonstrated the feasibility of using NMN as an endogenous probe to assess renal MATE function in humans with exposure to transporter inhibitors. Another study evaluated NMN and metformin pharmacokinetics in the presence and absence of trimethoprim. Healthy volunteers (n = 12) received metformin and underwent oral glucose tolerance tests [103]. With the exposure to trimethoprim for 5 days, metformin Cmax and AUC were increased between 20% and 30%, while renal clearance and creatinine clearance were decreased. Similar interaction results were observed for NMN following combination with trimethoprim. The authors reported good correlations between the endogenous (NMN) and exogenous (metformin) probes for renal clearance, which may support utilization of NMN in studies of MATE function in healthy volunteers.

      The clearance of additional endogenous compounds has been shown to be altered in the urine of healthy volunteers with or without pyrimethamine (50 mg) [104]. Significantly lower renal clearance of thiamine (70–84%) and carnitine (90–94%) into the urine was observed in volunteers receiving pyrimethamine, with no differences detected in plasma. The renal clearance of thiamine (50 ml/min) and carnitine (3 ml/min) also suggested reabsorption. Thiamine was previously reported to be a substrate of MATE1 and MATE2‐K from in vitro studies [27]. The endogenous compounds thiamine and carnitine may be helpful in assessing reabsorption function due to MATEs.

      A head‐to‐head study evaluated the performance of three endogenous compounds (creatinine, NMN, and N1‐methyladenosine) as biomarkers of MATE1/2‐K function [105]. Healthy subjects (n = 12) received metformin (500 mg) as the exogenous MATE probe and pyrimethamine as the MATE inhibitor in a crossover study design. The criteria for categorizing a well‐performing functional biomarker were based on whether changes in renal clearance as a function of pyrimethamine dose was correlated with metformin renal clearance changes. NMN and N1‐methyladenosine were superior to creatinine in reflecting inhibition of MATE1/2‐K (r 2 values of >0.5 vs 0.11, respectively). The study supported leveraging renal clearance of the endogenous biomarkers NMN and N1‐methyladenosine for MATE drug interaction assessments in healthy volunteers.

      The impact of genetic variation in SLC47A1 and SLC47A2 can impact both pharmacokinetics and pharmacodynamics.

      3.7.1 Metformin Pharmacokinetics

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