• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

利培酮和帕利哌酮在大鼠体内对 D₂ 和 5-HT（2A）受体占有率的药代动力学-药效学模型。

Pharmacokinetic-pharmacodynamic modeling of the D₂ and 5-HT (2A) receptor occupancy of risperidone and paliperidone in rats.

机构信息

Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD, Groningen, The Netherlands.

出版信息

Pharm Res. 2012 Jul;29(7):1932-48. doi: 10.1007/s11095-012-0722-8. Epub 2012 Mar 22.

DOI:10.1007/s11095-012-0722-8
PMID:22437487
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3369128/
Abstract

PURPOSE

A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D₂ and serotonin 5-HT(2A) receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats.

METHODS

A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D₂ and 5-HT(2A) RO data. A previously published physiology- and mechanism-based (PBPKPD) model describing brain concentrations and D₂ receptor binding in the striatum was expanded to include metabolite kinetics, active efflux from brain, and binding to 5-HT(2A) receptors in the frontal cortex.

RESULTS

A two-compartment model best fit to the plasma PK profile of risperidone and paliperidone. The expanded PBPKPD model described brain concentrations and D₂ and 5-HT(2A) RO well. Inclusion of binding to 5-HT(2A) receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern.

CONCLUSION

Binding to both D₂ and 5-HT(2A) receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D₂ and 5-HT(2A) receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.

摘要

目的

建立了一个药代动力学-药效学（PK-PD）模型，以描述非典型抗精神病药物利培酮和帕利哌酮在大鼠中的脑浓度、多巴胺 D₂ 和 5-羟色胺 5-HT(2A)受体占有率（RO）的时间过程。

方法

利用群体方法描述利培酮和帕利哌酮的 PK-PD，使用血浆和脑浓度以及 D₂ 和 5-HT(2A) RO 数据。先前发表的描述纹状体脑浓度和 D₂ 受体结合的基于生理学和机制的（PBPKPD）模型被扩展到包括代谢物动力学、脑内主动外排以及与额叶皮层中的 5-HT(2A)受体结合。

结果

两室模型最适合利培酮和帕利哌酮的血浆 PK 谱。扩展的 PBPKPD 模型很好地描述了脑浓度和 D₂ 和 5-HT(2A) RO。纳入与 5-HT(2A)受体的结合对于准确描述观察到的脑-血浆比是必要的。模拟表明，受体亲和力强烈影响脑-血浆比模式。

结论

与 D₂ 和 5-HT(2A)受体的结合影响利培酮和帕利哌酮在大脑中的分布。这可能源于它们对 D₂ 和 5-HT(2A)受体的高亲和力。在选择中枢活性药物的最佳 PK-PD 模型之前，可能需要考虑受体亲和力和脑-血浆比。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7596/3369128/ca12330ed992/11095_2012_722_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7596/3369128/79323fd6f3e4/11095_2012_722_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7596/3369128/ca12330ed992/11095_2012_722_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7596/3369128/79323fd6f3e4/11095_2012_722_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7596/3369128/ca12330ed992/11095_2012_722_Fig2_HTML.jpg

相似文献

1
Pharmacokinetic-pharmacodynamic modeling of the D₂ and 5-HT (2A) receptor occupancy of risperidone and paliperidone in rats.利培酮和帕利哌酮在大鼠体内对 D₂ 和 5-HT（2A）受体占有率的药代动力学-药效学模型。
Pharm Res. 2012 Jul;29(7):1932-48. doi: 10.1007/s11095-012-0722-8. Epub 2012 Mar 22.
2
Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human.基于生理学的建模方法预测抗精神病药在大脑中对多巴胺 D2 受体的占有率：从大鼠到人体的转化。
J Clin Pharmacol. 2019 May;59(5):731-747. doi: 10.1002/jcph.1365. Epub 2019 Jan 24.
3
Signalling profile differences: paliperidone versus risperidone.信号传导特征差异：帕利哌酮与利培酮对比
Br J Pharmacol. 2013 Oct;170(3):532-45. doi: 10.1111/bph.12295.
4
Distinct electrophysiological effects of paliperidone and risperidone on the firing activity of rat serotonin and norepinephrine neurons.帕利哌酮和利培酮对大鼠血清素和去甲肾上腺素能神经元放电活动的不同电生理效应。
Psychopharmacology (Berl). 2007 Sep;194(1):63-72. doi: 10.1007/s00213-007-0818-8. Epub 2007 May 27.
5
Pharmacokinetic-pharmacodynamic modeling of risperidone effects on electroencephalography in healthy volunteers.利培酮对健康志愿者脑电图影响的药代动力学-药效学建模
Psychopharmacology (Berl). 1999 Jun;144(3):272-8. doi: 10.1007/s002130051003.
6
A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats.阿哌沙班与依诺肝素治疗髋关节置换术后静脉血栓栓塞症的系统评价和网状 Meta 分析
Eur Psychiatry. 2010 Mar;25(2):92-100. doi: 10.1016/j.eurpsy.2009.05.008. Epub 2009 Jul 28.
7
Dopamine D2 receptor occupancy as a predictor of catalepsy in rats: a pharmacokinetic-pharmacodynamic modeling approach.多巴胺D2受体占有率作为大鼠僵住症的预测指标：一种药代动力学-药效学建模方法。
Pharm Res. 2014 Oct;31(10):2605-17. doi: 10.1007/s11095-014-1358-7. Epub 2014 May 3.
8
Relationship between dose, drug levels, and D2 receptor occupancy for the atypical antipsychotics risperidone and paliperidone.非典型抗精神病药利培酮和帕利哌酮的剂量、药物水平与 D2 受体占有率的关系。
J Pharmacol Exp Ther. 2012 Apr;341(1):81-9. doi: 10.1124/jpet.111.189076. Epub 2012 Jan 3.
9
Active cyamemazine metabolites in patients treated with cyamemazine (Tercian®): influence on cerebral dopamine D2 and serotonin 5-HT (2A) receptor occupancy as measured by positron emission tomography (PET).使用环丙嗪（Tercian®）治疗的患者中环丙嗪的活性代谢物：正电子发射断层扫描（PET）测量对大脑多巴胺 D2 和血清素 5-HT（2A）受体占有率的影响。
Psychopharmacology (Berl). 2011 Oct;217(3):315-21. doi: 10.1007/s00213-011-2289-1. Epub 2011 Apr 9.
10
Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat.大鼠体内利培酮及其活性代谢物9-羟基利培酮的脑区分布
Psychopharmacology (Berl). 1994 Feb;114(1):53-62. doi: 10.1007/BF02245444.

引用本文的文献

1
Long-Acting Injectable Antipsychotic Use and Discontinuation Rates in Children and Adolescents With Schizophrenia Using Medicaid Claims Data.利用医疗补助索赔数据研究精神分裂症儿童和青少年长效注射用抗精神病药物的使用及停药率
Early Interv Psychiatry. 2025 Jun;19(6):e70063. doi: 10.1111/eip.70063.
2
Pharmacokinetic/pharmacodynamic modeling of cortical dopamine concentrations after quetiapine lipid core nanocapsules administration to schizophrenia phenotyped rats.奎硫平脂质核纳米囊给药后精神分裂症表型大鼠皮质多巴胺浓度的药代动力学/药效学模型。
CPT Pharmacometrics Syst Pharmacol. 2024 Apr;13(4):638-648. doi: 10.1002/psp4.13107. Epub 2024 Jan 28.
3

本文引用的文献

1
Mechanism-based pharmacokinetic-pharmacodynamic modeling of the dopamine D2 receptor occupancy of olanzapine in rats.基于机制的奥氮平对大鼠多巴胺 D2 受体占有率的药代动力学-药效学模型。
Pharm Res. 2011 Oct;28(10):2490-504. doi: 10.1007/s11095-011-0477-7. Epub 2011 Jun 7.
2
Differential modulation of α-1 adrenoceptor subtypes by antidepressants in the rat brain.抗抑郁药在大鼠脑中对α-1 肾上腺素受体亚型的差异调节。
J Neural Transm (Vienna). 2010 Dec;117(12):1423-30. doi: 10.1007/s00702-010-0522-4. Epub 2010 Dec 7.
3
Piraña and PCluster: a modeling environment and cluster infrastructure for NONMEM.
Differential Effects of Neonatal Ventral Hippocampus Lesion on Behavior and Corticolimbic Plasticity in Wistar-Kyoto and Spontaneously Hypertensive Rats.
新生鼠腹侧海马损伤对 Wistar-Kyoto 大鼠和自发性高血压大鼠行为和皮质边缘可塑性的差异影响。
Neurochem Res. 2024 Apr;49(4):959-979. doi: 10.1007/s11064-023-04074-9. Epub 2023 Dec 29.
4
Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal.多巴胺动力学与抗精神病药物无反应的神经生物学：对难治性精神分裂症的相关性——系统评价与批判性评估
Biomedicines. 2023 Mar 14;11(3):895. doi: 10.3390/biomedicines11030895.
5
Enhancing the Antipsychotic Effect of Risperidone by Increasing Its Binding Affinity to Serotonin Receptor via Picric Acid: A Molecular Dynamics Simulation.通过苦味酸提高利培酮与血清素受体的结合亲和力以增强其抗精神病作用：分子动力学模拟
Pharmaceuticals (Basel). 2022 Feb 24;15(3):285. doi: 10.3390/ph15030285.
6
Risperidone is not only a prodrug: psychosis induced by medication switch from risperidone to paliperidone - a case report.利培酮不仅是前药：药物转换致精神症状案例报告，由利培酮换用帕利哌酮。
Eur J Hosp Pharm. 2023 Jul;30(4):e20. doi: 10.1136/ejhpharm-2021-002901. Epub 2021 Nov 16.
7
The Kinetic Component in Drug Discovery: Using the Most Basic Pharmacological Concepts to Advance in Selecting Drugs to Combat CNS Diseases.药物发现中的动力学成分：利用最基本的药理学概念来推进选择药物以对抗中枢神经系统疾病。
Curr Neuropharmacol. 2020;18(3):250-257. doi: 10.2174/1570159X17666191001144309.
8
CDI cross-linked β-cyclodextrin nanosponges of paliperidone: synthesis and physicochemical characterization.帕利哌酮交联 β-环糊精纳米海绵的合成及理化特性研究。
J Mater Sci Mater Med. 2019 Jun 13;30(6):74. doi: 10.1007/s10856-019-6268-0.
9
Impact of mathematical pharmacology on practice and theory: four case studies.数学药理学对实践和理论的影响：四个案例研究。
J Pharmacokinet Pharmacodyn. 2018 Feb;45(1):3-21. doi: 10.1007/s10928-017-9539-8. Epub 2017 Sep 7.
10
Pharmacogenomic Study Reveals New Variants of Drug Metabolizing Enzyme and Transporter Genes Associated with Steady-State Plasma Concentrations of Risperidone and 9-Hydroxyrisperidone in Thai Autism Spectrum Disorder Patients.药物基因组学研究揭示了与泰国自闭症谱系障碍患者中利培酮和9-羟基利培酮稳态血药浓度相关的药物代谢酶和转运蛋白基因的新变体。
Front Pharmacol. 2016 Dec 2;7:475. doi: 10.3389/fphar.2016.00475. eCollection 2016.
Piraña 和 PCluster：NONMEM 的建模环境和集群基础设施。
Comput Methods Programs Biomed. 2011 Jan;101(1):72-9. doi: 10.1016/j.cmpb.2010.04.018. Epub 2010 Jun 2.
4
Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid.脑匀浆和脑脊液中稳态下的游离药物浓度可作为脑间质液中游离浓度的替代指标。
Drug Metab Dispos. 2009 Apr;37(4):787-93. doi: 10.1124/dmd.108.024125. Epub 2008 Dec 30.
5
Validation of a rat in vivo [(3)H]M100907 binding assay to determine a translatable measure of 5-HT(2A) receptor occupancy.一种用于确定5-HT(2A)受体占有率可转化测量指标的大鼠体内[(3)H]M100907结合试验的验证。
Eur J Pharmacol. 2008 Sep 4;591(1-3):136-41. doi: 10.1016/j.ejphar.2008.06.063. Epub 2008 Jun 19.
6
Using pharmacokinetic-pharmacodynamic modelling as a tool for prediction of therapeutic effective plasma levels of antipsychotics.使用药代动力学-药效学模型作为预测抗精神病药物治疗有效血浆水平的工具。
Eur J Pharmacol. 2008 Apr 28;584(2-3):318-27. doi: 10.1016/j.ejphar.2008.02.005. Epub 2008 Feb 12.
7
Dose-finding study of paliperidone ER based on striatal and extrastriatal dopamine D2 receptor occupancy in patients with schizophrenia.基于纹状体和纹状体以外多巴胺D2受体占有率的帕利哌酮缓释片治疗精神分裂症患者的剂量探索性研究。
Psychopharmacology (Berl). 2008 Apr;197(2):229-35. doi: 10.1007/s00213-007-1029-z. Epub 2007 Dec 6.
8
The evolution of drug development in schizophrenia: past issues and future opportunities.精神分裂症药物研发的演进：过去的问题与未来的机遇
Neuropsychopharmacology. 2008 Aug;33(9):2061-79. doi: 10.1038/sj.npp.1301639. Epub 2007 Nov 28.
9
In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system.体外P-糖蛋白测定法用于预测P-糖蛋白在中枢神经系统中与药物的体内相互作用。
Drug Metab Dispos. 2008 Feb;36(2):268-75. doi: 10.1124/dmd.107.017434. Epub 2007 Oct 25.
10
Antipsychotic efficacy: relationship to optimal D2-receptor occupancy.抗精神病药物疗效：与最佳D2受体占有率的关系。
Eur Psychiatry. 2007 Jul;22(5):267-75. doi: 10.1016/j.eurpsy.2007.02.005. Epub 2007 Apr 6.