Association of clozapine-related metabolic disturbances with CYP3A4 expression in patients with schizophrenia

Author:

Menus Ádám,Kiss Ádám,Tóth Katalin,Sirok Dávid,Déri Máté,Fekete Ferenc,Csukly Gábor,Monostory Katalin

Abstract

AbstractClozapine is effective in treatment-resistant schizophrenia; however, adverse effects often result in discontinuation of clozapine therapy. Many of the side-effects are associated with pharmacokinetic variations; therefore, the expression of major clozapine-metabolizing enzymes (CYP1A2, CYP3A4) in patients may predict development of adverse effects. In patients with schizophrenia (N = 96), development of clozapine concentration-dependent metabolic side-effects was found to be associated with pharmacokinetic variability related to CYP3A4 but not to CYP1A2 expression. In low CYP3A4 expressers, significant correlation was detected between fasting glucose level and clozapine concentration; moreover, the incidence of abnormal glucose level was associated with exaggerated clozapine concentrations (> 600 ng/ml). In low CYP3A4 expressers, exaggerated concentrations were more frequently observed than in normal/high expressers. Moderate/high risk obesity (BMI ≥ 35) more frequently occurred in low CYP3A4 expresser patients than in normal/high expressers. In patients with normal/high CYP3A4 expression and consequently with extensive clozapine-metabolizing capacity, norclozapine/clozapine ratio correlated with fasting glucose levels, triglyceride concentrations and BMI. Low CYP3A4 expression often resulting in exaggerated clozapine concentrations was considered to be as an important risk factor for some concentration-dependent adverse effects as normal/high CYP3A4 expression evoking high norclozapine/clozapine ratios. CYP3A4-status can identify patients with increased risk for metabolic side-effects and prevent their development by careful therapeutic strategy.

Funder

Ministry for National Economy

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

Reference55 articles.

1. European Medicines Agency. Leponex. Summary of Product Characteristics. https://www.ema.europa.eu/en/documents/referral/summary-information-referral-opinion-following-arbitration-pursuant-article-30-council-directive/83/ec-leponex-associated-names-international-non-proprietary-name-inn-clozapine-background-inform_en.pdf (2002).

2. Kane, J., Honigfeld, G., Singer, J. & Meltzer, H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch. Gen. Psychiatry 45, 789–796 (1988).

3. Meltzer, H. Y. Treatment-resistant schizophrenia—the role of clozapine. Curr. Med. Res. Opin. 14, 1–20 (1997).

4. McEvoy, J. P. et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am. J. Psychiatry 163, 600–610 (2006).

5. Kapur, S., Zipursky, R. B. & Remington, G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am. J. Psychiatry 156, 286–293 (1999).

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3