Quantification of the steady-state plasma concentrations of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia using a novel HPLC method and the effects of CYPs and ABC transporters polymorphisms
Quantification of the steady-state plasma concentrations of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia using a novel HPLC method and the effects of CYPs and ABC transporters polymorphisms
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DOI：
10.1177/0004563216686377
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发表时间：
2017-11-01
影响因子：
2.2
通讯作者：
Miura, Masatomo
中科院分区：
文献类型：
--
作者：
Akamine, Yumiko;Sugawara-Kikuchi, Yuka;Miura, Masatomo
本研究建立了一种同时测定人血浆中氯氮平及其活性代谢物N-去甲基氯氮平的高效液相色谱（HPLC）法，并考察了细胞色素P450（CYP）2D 6、CYP 3A 5、ABCB 1和ABCG 2基因多态性等因素对该方法的影响，对日本精神分裂症患者氯氮平和N-去甲基氯氮平稳态血浆谷浓度（C-0）的影响。的cyp 2d 6（CYP2D 6 *2、CYP2D 6 *5、CYP2D 6 *10）、CYP3A 5（CYP3A5*3）、ABCB 1方法采用聚合酶链反应（PCR）方法，检测1236 C>T、2677 G>T/A、3435 C>T和ABCG 2基因型（421 C>A）。在10 ~ 2500 ng/mL的线性范围内，准确度均在9.0%以内，定量限均为10 ng/mL。携带ABCG 2 421 A等位基因的患者的氯氮平中位C-0/剂量（C-0/D）比值显著高于携带421 C/C基因型的患者（P=0.010）。而ABCB 1、CYP 2D 6和CYP 3A 5基因型间氯氮平和N-去甲基氯氮平的C-0/D比值无显著性差异。多因素回归分析显示，ABCG 2基因多态性与氯氮平的C-0/D比值相关（R-2=0.139，P=0.016）。在开始治疗前了解患者的ABCG 2 421 C>A基因型可能有助于做出旨在实现最佳氯氮平暴露的剂量决定。
Background This study developed a novel high-performance liquid chromatography (HPLC) method for the simultaneous quantification of clozapine and its active metabolite, N-desmethylclozapine, in human plasma and investigated the effects of various factors, including genetic polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A5, ABCB1 and ABCG2, on the steady-state plasma trough concentrations (C-0) of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia.Methods Forty-five patients had been receiving fixed doses of clozapine for at least four weeks. The CYP2D6 (CYP2D6*2, CYP2D6*5, CYP2D6*10), CYP3A5 (CYP3A5*3), ABCB1 (1236C>T, 2677G>T/A, 3435C>T) and ABCG2 (421C>A) genotypes were identified by polymerase chain reaction.Results The within- and between-day coefficients of variation (CV) were less than 11.0%, and accuracy was within 9.0% over the linear range from 10 to 2500ng/mL for both analytes, and their LOQs were each 10ng/mL. The median C-0/dose (C-0/D) ratios of clozapine were significantly higher in patients with the ABCG2 421A allele than in those with the 421C/C genotype (P=0.010). However, there were no significant differences in C-0/D ratios of clozapine and N-desmethylclozapine among ABCB1, CYP2D6 or CYP3A5 genotypes. In multiple regression analysis, including polymorphisms, age, body weight and biochemical data of patients, the ABCG2 polymorphism alone was correlated with the C-0/D ratios of clozapine (R-2=0.139, P=0.016).Conclusions Among the various CYPs and drug transporters, BCRP appeared to most strongly influence clozapine exposure. Knowledge of the patient's ABCG2 421C>A genotype before initiating therapy may be useful when making dosing decisions aimed at achieving optimal clozapine exposure.