Results: 5

1.
Figure 1

Figure 1. Representative cartoon of metformin transporters in the hepatocyte of the liver and nephron of the kidney. From: The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin.

This cartoon shows the liver (top left) and nephron (bottom left) and the cation transporters in the hepatocyte (top right) and proximal tubule cell (bottom right) that have been identified as important determinants of the pharmacokinetics and response to metformin. MATE2 in the kidney has two functional isoforms, MATE2 and MATE2-K.

Sophie L. Stocker, et al. Clin Pharmacol Ther. ;93(2):186-194.
2.
Figure 2

Figure 2. The effect of MATE1 (g.−66T>C) on the pharmacokinetics of metformin in 57 healthy volunteers. From: The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin.

Shown is the mean plasma concentration-time curve of metformin after oral administration to healthy volunteers who carry at least one MATE1 (g.−66T>C) variant allele (n=25, open circles) or those who are homozygous for the reference MATE1 alleles (n=32, closed circles). The volunteers were given two doses of metformin (1850 mg in total). The plasma metformin concentration-time curves after the second dose are shown. Data represent mean ± SEM.

Sophie L. Stocker, et al. Clin Pharmacol Ther. ;93(2):186-194.
3.
Figure 4

Figure 4. The effect of MATE2 (g.−130G>A) on the pharmacokinetics of metformin in 57 healthy volunteers. From: The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin.

The plasma concentration-time curves of metformin after oral administration to healthy volunteers (a) who carry at least one MATE2 variant allele (n=30, open circles) or those who carry only MATE2 reference alleles (n=27, closed circles) and carry either the reference or variant alleles of MATE1 or (b) who carry at least one MATE2 variant allele (n=17, open triangles) or those who carry only MATE2 reference alleles (n=15, closed triangles) and only carry both reference alleles for MATE1. Data represent mean ± SEM; *P<0.05 compared with volunteers with at least one reference allele. The renal clearance (c) and net tubular secretion (e) of the same volunteers (open boxes) depicted in (a). The renal clearance (d) and net tubular secretion (f) of the same volunteers (shaded boxes) depicted in (b). The box plots (c-f) display the median and interquartile range (the 25th–75th percentile). The whiskers display lower and upper values within 1.5 times the interquartile range beyond the 25th and 75th percentile. The renal secretion of metformin was calculated by subtracting the clearance of creatinine from the renal clearance of metformin. The volunteers were given two doses of metformin (1850 mg in total). The plasma metformin concentration-time curves after the second dose are shown.

Sophie L. Stocker, et al. Clin Pharmacol Ther. ;93(2):186-194.
4.
Figure 5

Figure 5. MATE2 genetic variants are associated with different response to metformin in healthy volunteers and type II diabetic patients. From: The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin.

(a) The time course of plasma glucose concentrations after an OGTT during metformin treatment in healthy volunteers carrying at least one reference MATE2 (n=49, closed circles) and those carrying both MATE2 variant (n=8, open circles) alleles. The data are expressed as mean ± SEM; *P<0.05 compared with volunteers with at least one reference allele. (b) The glucose exposure with OGTT (AUC) after metformin treatment for healthy volunteers represented in (b). (c) The relative change in glycosylated hemoglobin (HbA1c) in Caucasian (n=189) and African American (n=64) type II diabetes patients receiving metformin monotherapy who are reference for the MATE2 reduced-function coding variant (c.485C>T) and carrying at least one reference MATE2 allele (n=232) or homozygous for the MATE1 variant allele (n=16). Relative change in HbA1c was calculated as follows: (treatment minus baseline HbA1c)/baseline HbA1c. Relative change of −0.15 is interpreted as a decrease in HbA1c level by 15% from baseline. The box plots (b, c) display the median and interquartile range (the 25th–75th percentile). The whiskers display lower and upper values within 1.5 times the interquartile range beyond the 25th and 75th percentile.

Sophie L. Stocker, et al. Clin Pharmacol Ther. ;93(2):186-194.
5.
Figure 3

Figure 3. The MATE1 promoter variant (g.−66T>C) is associated with different response to metformin in healthy volunteers and type II diabetic patients. From: The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin.

(a) The time course of plasma glucose concentrations after an oral glucose tolerance test (OGTT) during metformin treatment in healthy volunteers carrying at least one reference MATE1 (n=49, closed circles) and those carrying both MATE1 variant (n=8, open circles) alleles. The data are expressed as mean ± SEM; *P<0.05 compared with volunteers with at least one reference allele. (b) The glucose exposure with OGTT (AUC) after metformin treatment in the same healthy volunteers represented in (a). (c) The relative change in glycosylated hemoglobin (HbA1c) in diabetes patients (n=145) receiving metformin monotherapy who are homozygous for the major alleles of OCT1 and carrying at least one reference MATE1 allele (n=122) or homozygous for the MATE1 variant allele (n=23). Relative change in HbA1c was calculated as follows: (treatment minus baseline HbA1c)/baseline HbA1c. Relative change of −0.15 is interpreted as a decrease in HbA1c level by 15% from baseline. The box plots (b and c) display the median and interquartile range (the 25th–75th percentile). The whiskers display lower and upper values within 1.5 times the interquartile range beyond the 25th and 75th percentile.

Sophie L. Stocker, et al. Clin Pharmacol Ther. ;93(2):186-194.

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