Transl Clin Pharmacol.  2016 Dec;24(4):194-202. 10.12793/tcp.2016.24.4.194.

Screening study for genetic polymorphisms affecting pharmacokinetics of pioglitazone

• Yun JY
• Kim BH
• Lee JH
• Lee K
• Kwack K
• Yim SV

• KMID: 2413842
• DOI: http://doi.org/10.12793/tcp.2016.24.4.194

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 C(max), 1,118 significant SNPs (P < 0.0001) in T(max) and 1,259 significant SNPs (P < 0.0001) in AUC(inf) 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 C(max). In the T(max) 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 AUC(inf) 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.

Keyword

Pharmacogenomics; Pioglitazone; Pharmacokinetics; Single nucleotide polymorphism; Phase I and II drug metabolizing enzyme

MeSH Terms

Absorption
Cytochrome P-450 CYP1A1
DNA
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Genome
Genotype
Humans
Insulin Resistance
Linear Models
Male
Mass Screening*
Pharmacogenetics
Pharmacokinetics*
Polymorphism, Genetic*
Polymorphism, Single Nucleotide
PPAR gamma
Therapeutic Equivalency
Volunteers
Cytochrome P-450 CYP1A1
DNA
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
PPAR gamma

Figure

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  Figure 1. Results of regression analysis of in Cmax group.

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  Figure 2. Results of regression analysis of in Tmax group.

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  Figure 3. Results of regression analysis of in AUCinf group.

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