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Yun, Kim, Lee, Lee, Kwack, and Yim: Screening study for genetic polymorphisms affecting pharmacokinetics of pioglitazone
Original Article

Translational and Clinical Pharmacology 2016;24(4):194-202.

Published online: 19 January 2016

DOI: https://doi.org/10.12793/tcp.2016.24.4.194

Screening study for genetic polymorphisms affecting pharmacokinetics of pioglitazone

Ji Young Yun1, Bo-Hyung Kim1, Ji Hyun Lee1, Kidong Lee2, KyuBum Kwack2, Sung-Vin Yim∗, 1

1Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul 02447, Korea

2Department of BioMedical Science, College of Life Science, CHA University, SeongNam 13496, Republic of Korea

∗Correspondence: S-V. Yim; Tel: +82-2-958-9567, Fax: +82-2-958-9559, E-mail: ysvin@khu.ac.kr, K. B. Kwack; Tel: +82-01-4416-3704, E-mail: kbkwack@cha.ac.kr

Received 27 Nov 2016       Revised 12 December 2016       Accepted 12 December 2016

Copyright © 2016 Korean Society for Clinical Pharmacology and Therapeutics

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Pioglitazone is known to have antidiabetic effects through decreasing peripheral, hepatic and vascular insulin resistance by the stimulation of PPAR gamma. To address the possible genetic factors affecting the pharmacokinetics (PK) of pioglitazone, 27 male Korean volunteers were enrolled from two separate bioequivalence studies. Each subject was administered 15 mg pioglitazone and reference drug PK parameters were used. We used Illumina Human610 Quad v1.0 DNA Analysis BeadChip for whole genome SNPs analysis and whole genome genotyping data was processed by linear regression analysis for PK parameters. We found 35 significant SNPs (P < 0.0001) in Cmax, 1,118 significant SNPs (P < 0.0001) in Tmax and 1,259 significant SNPs (P < 0.0001) in AUCinf from whole genome analysis. For clinical pharmacological purpose, we selected SNPs from several phase I and II drug metabolizing enzyme and analyzed PK parameters with genotypes. Four SNPs (rs7761731 and rs3799872 from CYP39A1; rs156697 from GSTO2; rs1558139 from CYP4F2) showed significant associations with pioglitazone Cmax. In the Tmax group, seven SNPs from 3 genes (rs3766198 from CYP4B1; rs2270422 from GSTZ1; rs2054675, rs10500282, rs3745274, rs8192719, and rs11673270 from CYP2B6) had significant associations. In the AUCinf group, seven SNPs from 4 genes (rs11572204 from CYP2J2; rs4148280 from UGT2A1, rs4646422 from CYP1A1; rs3745274, rs8192719, rs11673270, and rs707265 from CYP2B6) showed significant associations with pioglitazone absorption. These results showed that genetic makeup could affect the PK parameters and these informations could be provide information for personalized pioglitazone therapy.

Keywords: Pharmacogenomics, Pioglitazone, Pharmacokinetics, Single nucleotide polymorphism, Phase I and II drug metabolizing enzyme

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Figure 1.
Results of regression analysis of in Cmax group.
tcp-24-194f1.tif
Figure 2.
Results of regression analysis of in Tmax group.
tcp-24-194f2.tif
Figure 3.
Results of regression analysis of in AUCinf group.
tcp-24-194f3.tif
Table 1.
Demographic characteristics and reference pioglitazone pharmacokinetics parameters of volunteers
Subject No. Age (year) Sex (M/F) Weight (kg) Height (cm) Actos 15 mg (one tablets of 15 mg pioglitazone, Lilly Korea Co., Ltd.)
Cmax (ng/ml) Tmax (h) AUCt (ng·h/ml) AUCinf (ng·h/ml)
1 22 M 71.5 185 946.3 1 8353.6 8915.2
2 33 M 60.7 166 579.7 4 14337.8 24413
3 26 M 77.8 175 539.1 1 4514.7 4741
4 24 M 69.5 178 847.6 1 6968.6 7360.5
5 24 M 87.7 172 584.4 1.5 6204.2 6522
6 37 M 64.5 177 522.6 2 5644.3 6095.7
7 33 M 68.3 157 608.8 1.5 6293.9 6910.6
8 28 M 70.7 177 642.7 1.5 7797.1 8477.2
9 24 M 59.3 177 1178.3 1 8077.5 8558.4
10 27 M 79 178 383.8 2 3827 4760.4
11 23 M 64 173 841.9 2 10027.2 11904.2
12 21 M 74.7 179 850.4 1 9603.6 10345.9
13 21 M 70.3 170 634.8 1 6384.8 7482
14 21 M 53.8 166 1331.1 1.5 12342.1 13660
15 26 M 63.8 171 738.2 1 5724.9 6332.5
16 25 M 68.7 169.7 990 1.5 7362.2 7519.1
17 25 M 64 177 1082.2 2 8973.5 9527.2
18 25 M 84.5 171 729.4 1 6275.4 6865.8
19 23 M 65.8 164.4 1044.4 2 8086.1 8325.9
20 25 M 87.9 187 644.9 2 9384.3 10432.5
21 25 M 82.5 178.4 851.7 2 7476.6 7615
22 28 M 72.8 177 816.4 1 4608.1 4912.1
23 24 M 67.5 169.1 665.7 2 6620.2 8263.3
24 23 M 75.5 178.3 797.1 2 8242.1 9705.8
25 36 M 66.3 166 332.2 2.5 3186.6 3444.9
26 25 M 63 174 745.6 2 5313 5415.7
27 23 M 63.4 176 792.3 1 8065.5 9249.6
Mean ± SD 26 ± 4.3   70.3 ± 8.6 173.7 ± 6.5 767.5 ± 230.2 1.6 ± 0.67 7396.1 ± 2453.5 8435.4 ± 3929.8

Abbreviation: M, male; F, female; Cmax, maximum measured plasma concentration; Tmax, time of the maximum measured plasma concentration; AUCt, area under the plasma concentration-time curve from time zero to time of last measurable concentration; AUCinf, area under the plasma concentration-time curve from zero to infinity; SD, standard deviation.

Table 2.
Summary of regression analysis
    N
Cmax P <0.0001 35
0.0001 ~ <0.001 468
<0.01 5,089
Tmax P <0.0001 1,118
0.0001 ~ <0.001 527
0.001 ~ <0.01 4,541
AUCinf P <0.0001 1,259
0.0001 ~ <0.001 1,140
0.001 ~ <0.01 5,098

N=number

Table 3.
Selected SNPs of Phase I and II drug metabolizing enzymes in Cmax group from linear regression analysis
Marker Chr. Location Gene Genotype N Mean Stdev. P
rs7761731 6 missense CYP39A1 AA 9 636.091 190.301 0.005∗∗
      TA 13 775.532 181.510  
      TT 5 982.968 275.762  
rs3799872 6 intron CYP39A1 CC 8 639.504 203.146 0.004∗∗
      TC 13 746.211 174.641  
      TT 6 984.135 246.665  
rs156697 10 missense GSTO2 CC 2 987.680 269.563 0.009∗∗
      TC 7 910.693 251.258  
      TT 18 687.298 183.096  
rs1558139 19 intron CYP4F2 AA 2 483.500 213.999 0.007∗∗
      AG 16 725.477 171.676  
      GG 9 905.217 257.265  

Chr, chromosome; N, number; Stdev, standard deviation. ∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001

Table 4.
Selected SNPs of Phase I and II drug metabolizing enzymes in Tmax group from linear regression analysis
Marker Chr. Location Gene Genotype N Mean Stdev. P
rs3766198 1 intron CYP4B1 GG 11 2.045 0.757 0.006∗∗
      TG 11 1.409 0.437  
      TT 5 1.200 0.447  
rs2270422 14 intron GSTZ1 CC 7 2.143 0.900 0.004∗∗
      CG 12 1.625 0.528  
      GG 8 1.188 0.259  
rs2054675 19 flanking_5UTR CYP2B6 CC 2 3.000 1.414 0.002∗∗
      TC 9 1.722 0.441  
      TT 16 1.406 0.491  
rs10500282 19 intron CYP2B6 CC 2 3.000 1.414 0.002∗∗
      TC 9 1.722 0.441  
      TT 16 1.406 0.491  
rs3745274 19 missense CYP2B6 GG 17 1.441 0.496 0.004∗∗
      TG 8 1.688 0.458  
      TT 2 3.000 1.414  
rs8192719 19 intron CYP2B6 CC 17 1.441 0.496 0.004∗∗
      TC 8 1.688 0.458  
      TT 2 3.000 1.414  
rs11673270 19 intron CYP2B6 AA 17 1.441 0.496 0.004∗∗
      AC 8 1.688 0.458  
      CC 2 3.000 1.414  

Chr, chromosome; N, number; Stdev, standard deviation. ∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001

Table 5.
Selected SNPs of Phase I and II drug metabolizing enzymes in AUCinf group from linear regression analysis
Marker Chr. Location Gene Genotype N Mean Stdev. P
rs11572204 1 intron CYP2J2 CC 22 7526.019 2303.326 0.006∗∗
      CG 2 10804.994 1554.542  
      GG 3 13524.397 9502.091  
rs4148280 4 intron UGT2A1 CC 16 7184.061 1870.072 0.003∗∗
      TC 7 8063.100 2900.045  
      TT 4 14092.233 6942.204  
rs4646422 15 missense CYP1A1 AA 2 17422.783 9885.719 0.009∗∗
      AG 8 7954.883 2328.169  
      GG 17 7604.174 2381.115  
rs3745274 19 missense CYP2B6 GG 17 7521.493 1970.203 0.004∗∗
      TG 8 7946.620 2828.162  
      TT 2 18158.632 8845.072  
rs8192719 19 intron CYP2B6 CC 17 7521.493 1970.203 0.004∗∗
      TC 8 7946.620 2828.162  
      TT 2 18158.632 8845.072  
rs11673270 19 intron CYP2B6 AA 17 7521.493 1970.203 0.004∗∗
      AC 8 7946.620 2828.162  
      CC 2 18158.632 8845.072  
rs707265 19 flanking_3UTR CYP2B6 AA 4 6697.185 1682.872 0.010∗
      AG 12 6631.089 1792.361  
      GG 11 11035.799 4818.251  

Chr, chromosome; N, number; Stdev, standard deviation. ∗p value<0.05, ∗∗p value<0.01, ∗∗∗p value<0.001

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