RESUMEN
BACKGROUND AND OBJECTIVES: 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. PARTICIPANTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Asunto(s)
Pueblo Asiatico/genética , Redes Reguladoras de Genes , Hipoglucemiantes/administración & dosificación , Polimorfismo de Nucleótido Simple , Tiazolidinedionas/administración & dosificación , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Administración Oral , Adulto , Pueblo Asiatico/etnología , China/etnología , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP3A/genética , Femenino , Genotipo , Humanos , Hipoglucemiantes/farmacocinética , Masculino , Variantes Farmacogenómicas , Pioglitazona , Tiazolidinedionas/farmacocinética , Adulto JovenRESUMEN
Mizolastine is a selective histamine H1 receptor antagonist for chronic urticaria or allergic rhinitis. We investigated whether the variant genotypes of metabolic enzymes UGT1A1, CYP3A5 and transporter ABCB1 influence pharmacokinetic phenotype of substrate mizolastine in Chinese volunteers. Genotyping of single nucleotide polymorphisms in UGT1A1*6 (G211A), CYP3A5*3 (A6986G) and ABCB1 (C3435T) was determined by the pyrosequencing method. After a single oral dose of 10 mg mizolastine, the plasma concentrations were measured using validated high-performance liquid chromatography in 24 Chinese healthy volunteers. The results showed that the distributions of wild-type homozygotes and variant allele carriers (the sum of variant heterozygotes and variant homozygotes) were as follows: 17 cases (70.8%) versus seven cases (29.2%) in UGT1A1*6 genotypes, five cases (20.8%) versus 19 cases (79.2%) in CYP3A5*3 genotypes and seven cases (29.2%) versus 17 cases (70.8%) in ABCB1 3435T genotypes, respectively. There were no significant differences in pharmacokinetic parameters of mizolastine between the variant allele UGT1A1*6, CYP3A5*3 and ABCB1 3435T carriers and the wild-type homozygotes, and the ratios were as follows: Cmax was 101.03%, 86.02% and 105.78%; Tmax was 162.35%, 98.98% and 144.90%; AUC0-28 was 113.04%, 77.35% and 112.71%; and t1/2 was 95.77%, 72.40% and 100.97%, respectively. In conclusion, these results suggested that the UGT1A1, CYP3A5 and ABCB1 genetic polymorphisms might be not contributed to the interindividual variation of mizolastine pharmacokinetic phenotype in the Chinese population.
RESUMEN
Cytochrome P450 2W1 (CYP2W1) is expressed specially in certain cancers and could metabolize some substances into cytotoxic antitumor drugs in Caucasian ethnic population. To investigate the genetic polymorphism of CYP2W1 in Chinese, all the nine exons and exon-intron junctions were sequenced by dideoxy chain termination method among 385 Chinese subjects (including 223 Han and 162 Uygur). The present results showed that 40 single nucleotide polymorphisms (SNPs) were detected (14 in the exons and 26 in the introns), 10 were novel variants of which in Chinese. There were 7 novel SNPs in the exons and other 3 novel SNPs in the introns. Four of the 6 novel non-synonymous variations in exons, 131T > C (Leu44Pro), 1289C > A (Ala88Glu), 2027G > A (Arg187Gln) and 5070C > T (Thr383Met) were computationally predicted to affect CYP2W1 protein function, in spite of these variants were heterozygotes. Moreover, the allele frequencies in 6 known SNPs including CYP2W1*2 (2008G > A) and CYP2W1*3 (173A > C) were analyzed, which were significantly lower in Chinese Han (2.9% and 0.0%, respectively) and Uygur (5.2% and 0.0%, respectively) individuals, than those reported previously in Caucasians (9.1% and 33.1%, respectively, P < 0.05). These data provide useful information on the pharmacogenetic studies of CYP2W1 among Chinese and other ethnic populations.