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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.

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

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