Influences of CYP2D6*10 polymorphisms on the pharmacokinetics of iloperidone and its metabolites in Chinese patients with schizophrenia: a population pharmacokinetic analysis

被引：10

作者：

Pei, Qi ^{[1
,2
]}

Huang, Lu ^{[1
,2
]}

Huang, Jie ^{[1
,2
]}

Gu, Jing-kai ^{[3
]}

Kuang, Yun ^{[1
,2
]}

Zuo, Xiao-cong ^{[1
,2
]}

Ding, Jun-jie ^{[4
]}

Tan, Hong-yi ^{[1
,2
]}

Guo, Cheng-xian ^{[1
,2
]}

Liu, Shi-kun ^{[1
,2
]}

Yang, Guo-ping ^{[1
,2
]}

机构：

[1] Cent S Univ, Xiangya Hosp 3, Ctr Clin Pharmacol, Changsha 410013, Hunan, Peoples R China

[2] Cent S Univ, Xiangya Hosp 3, Dept Pharm, Changsha 410013, Hunan, Peoples R China

[3] Jilin Univ, Drug Metab Res Ctr, Changchun 130012, Peoples R China

[4] Fudan Univ, Childrens Hosp, Shanghai 200032, Peoples R China

来源：

ACTA PHARMACOLOGICA SINICA | 2016年 / 37卷 / 11期

基金：

对外科技合作项目（国际科技项目）; 中国国家自然科学基金;

关键词：

schizophrenia; iloperidone; gene polymorphisms; CYP2D6*10; population pharmacokinetics; HUMAN PLASMA; MASS-SPECTROMETRY; RISPERIDONE; CYP2D6; DISORDERS; FREQUENCY; PROFILE; ALLELE;

D O I：

10.1038/aps.2016.96

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Aim: Iloperidone is an atypical antipsychotic drug that is mainly metabolized by CYP2D6, CYP3A4, and cytosolic enzymes. Previous studies show that extensive and poor metabolizers of CYP2D6 exhibit different plasma concentrations of iloperidone and its metabolites. The aim of this study was to develop a parent-metabolite population pharmacokinetic (PPK) model to quantify the effects of CYP2D6*10 allele on the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients. Methods: Seventy Chinese schizophrenia patients were enrolled, from whom limited blood samples were collected on d 15 (0 h) and d 28 (0, 4 and 12 h after drug administration). The plasma concentrations of iloperidone and its metabolites M-1 (P-88) and M-2 (P-95) were simultaneously detected using a validated HPLC-MS assay. CYP2D6*10 (rs1065852) genotyping was performed. A PPK model was developed based on data from the patients using the NONMEM software (version 7.2). A one-compartment model with first-order absorption and elimination was used to describe the pharmacokinetic data related to iloperidone and its metabolites. Results: Patients with the CYP2D6*10 T/T genotype had significantly higher concentrations of iloperidone and M1, and lower concentrations of M2 than the patients with C/C or C/T genotypes. The CYP2D6*10 genotype affected the elimination constants for transformation of iloperidone to the metabolites M-1 (K-23) and M-2 (K-24). The K-23 value of the patients with T/T genotype was 1.34-fold as great as that of the patients with C/C or C/T genotype. The K-24 value of the patients with C/T and T/T genotypes was 0.693- and 0.492-fold, respectively, as low as that of the patients with C/C genotype. Conclusion: CYP2D6*10 mutations affect the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients, suggesting that the clinical doses of iloperidone for patients with CYP2D6*10 mutations need to be optimized.

引用

页码：1499 / 1508

页数：10