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Effects of functional CYP2C8,CYP2C9,CYP3A5,and ABCB1 genetic variants on the pharmacokinetics of insulin sensitizer pioglitazone in Chinese Han individuals
- Source :
- Pharmacogenetics and Genomics. 27:125-134
- Publication Year :
- 2017
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2017.
-
Abstract
- Pioglitazone is a thiazolidinedione antihyperglycemic drug with insulin-sensitizing properties. We investigated whether the variant genotypes of cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP3A5 and transporter ABCB1 influence the pharmacokinetic phenotype of the substrate pioglitazone in Chinese individuals.Single-nucleotide polymorphisms were determined by the PCR-restriction fragment length polymorphism method in 244 (CYP2C8 and CYP2C9) healthy Chinese Han individuals. After a single oral dose of 30 mg pioglitazone, the plasma concentrations of the parent drug and of two major active metabolites M-III and M-IV were measured using a validated LC-MS/MS in 21 (genotyping CYP3A5 and ABCB1) of these 244 volunteers.The results confirmed that the unique frequencies of CYP2C8*2 (0.0%), CYP2C8*3 (0.0%), and CYP2C9*2 (0.0%) alleles were significantly different from those reported in Whites and Africans, and there were only 10 variant CYP2C9*1/*3 heterozygous (CYP2C9*3 carriers) among 244 Chinese individuals. These results were similar to those reported in Asian ethnic populations, including the Chinese. Unexpectedly, the pioglitazone AUC0-48 in CYP2C9*3 carriers was lower (50.8%), whereas the AUC0-48 ratios of metabolites M-III/pioglitazone and M-IV/pioglitazone increased to 134.3 and 155.8%, respectively, compared with the wild-type CYP2C9*1/*1 homozygous. Moreover, this phenomenon was not observed in individuals with genetic variants of CYP3A5*3 and ABCB1 (C1236T).The present research suggests that the CYP2C8, CYP3A5, and ABCB1 genes play no significant role in the interindividual variation of pioglitazone pharmacokinetics, whereas CYP2C9*3 carriers are likely to accelerate the metabolism of this antidiabetic drug in the Chinese Han ethnic population.
- Subjects :
- Adult
Male
China
ATP Binding Cassette Transporter, Subfamily B
Genotype
Pharmacogenomic Variants
medicine.drug_class
medicine.medical_treatment
Administration, Oral
Pharmacology
Biology
Polymorphism, Single Nucleotide
030226 pharmacology & pharmacy
Cytochrome P-450 CYP2C8
Young Adult
03 medical and health sciences
0302 clinical medicine
Asian People
Pharmacokinetics
Genetics
medicine
Cytochrome P-450 CYP3A
Humans
Hypoglycemic Agents
Gene Regulatory Networks
General Pharmacology, Toxicology and Pharmaceutics
Thiazolidinedione
CYP3A5
CYP2C8
Molecular Biology
CYP2C9
Genetics (clinical)
Cytochrome P-450 CYP2C9
Pioglitazone
Insulin
030220 oncology & carcinogenesis
Molecular Medicine
Female
Thiazolidinediones
medicine.drug
Subjects
Details
- ISSN :
- 17446872
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Pharmacogenetics and Genomics
- Accession number :
- edsair.doi.dedup.....26e7d3a1bd571d81828a21bed5013367