本文選題：伊潘立酮 + 藥動(dòng)學(xué)�。� 參考：《中南大學(xué)》2014年碩士論文

【摘要】：一、目的 (1)研究伊潘立酮及代謝產(chǎn)物在中國(guó)健康志愿者中的藥動(dòng)學(xué)特征； (2)建立伊潘立酮干預(yù)精神分裂癥病患者群體藥動(dòng)學(xué)模型,獲得群體藥動(dòng)學(xué)參數(shù),評(píng)價(jià)群體參數(shù)的影響因素； (3)研究CYP2D6*10(rs1065852)基因型對(duì)伊潘立酮及代謝產(chǎn)物血藥濃度和藥動(dòng)學(xué)參數(shù)的影響。 二、方法 (1)按入選／排除標(biāo)準(zhǔn)篩選中國(guó)健康志愿者16例,進(jìn)行隨機(jī)、開(kāi)放、兩劑量(lmg、3mg)、雙周期叉試驗(yàn)。洗脫期14天。采取給藥前及給藥后0.5、1、1.5、2、3、4、6、8、12、24、36、48、72、96和120h系列血樣,HPLC-MS/MS法測(cè)定伊潘立酮及代謝產(chǎn)物(M1,M2)血藥濃度,WinNolin軟件計(jì)算藥動(dòng)學(xué)參數(shù),SPSS18.0軟件進(jìn)行統(tǒng)計(jì)分析。 (2)按入選/排標(biāo)準(zhǔn)篩選精神分裂癥患者70例,收集基本信息；采集連續(xù)給藥(劑量滴定后)第15天,第28天谷濃度及第28天給藥后4、12h血樣;HPLC-MS/MS法測(cè)定伊潘立酮及代謝產(chǎn)物(M1,M2)血藥濃度；SPSS18.0對(duì)數(shù)據(jù)進(jìn)行統(tǒng)計(jì)分析,NONMEM軟件建立群體藥動(dòng)學(xué)模型。 (3)收集完成藥動(dòng)學(xué)研究健康志愿者(14名)和精神分裂癥患者(70名)血液樣本,提取外周淋巴細(xì)胞DNA,基因測(cè)序法對(duì)CYP2D6*10(rs1065852)進(jìn)行基因分型,SPSS18.0對(duì)基因型與血藥濃度、藥動(dòng)學(xué)參數(shù)進(jìn)行相關(guān)性分析。 三、結(jié)果 (1)口服伊潘立酮片后,伊潘立酮、M1符合二室模型,M2符合一室模型。伊潘立酮主要藥動(dòng)學(xué)參數(shù)Cmax、AUC、CL/F在劑量間、個(gè)體間差異有統(tǒng)計(jì)學(xué)意義；伊潘立酮的AUC和Cmax的增加不呈劑量比例關(guān)系；健康志愿者服用伊潘立酮片后不良反應(yīng)發(fā)生率高。 (2)群體藥動(dòng)學(xué)模型顯示,引入變量可部分解釋個(gè)體間差異：CYP2D6*10突變影響伊潘立酮經(jīng)其他途徑消除速率常數(shù)(K20)和M2生成速率(K24),K20和K24個(gè)體間差異分別下降1.8%和7%；紅細(xì)胞數(shù)(RBC)引入模型后,伊潘立酮分布容積V2的個(gè)體差異下降1.3%。 (3)健康志愿者和精神分裂癥患者中CYP2D6*10基因型頻率分別為21.4%和24.3%；精神分裂癥患者中CYP2D6*10TT攜帶者伊潘立酮和M1濃度／劑量校正值升高,而M2的校正值降低；健康志愿者CYP2D6*10基因型組間藥動(dòng)學(xué)參數(shù)差異無(wú)統(tǒng)計(jì)學(xué)意義。 四、結(jié)論 (1)單次口服lmg和3mg劑量時(shí),伊潘立酮在中國(guó)健康志愿者中藥動(dòng)學(xué)參數(shù)增加與劑量不呈比例關(guān)系,部分藥動(dòng)學(xué)參數(shù)高于國(guó)外報(bào)道,耐受劑量低,不良反應(yīng)發(fā)生率高。 (2)本研究建立的伊潘立酮群體藥動(dòng)學(xué)模型顯示CYP2D6*10突變和紅細(xì)胞數(shù)可降低群體參數(shù)K20、K24和V2的個(gè)體間變異,能部分解釋伊潘立酮清除和分布的個(gè)體間變異。 (3)CYP2D6*10(rs1065852)基因型影響伊潘立酮干預(yù)精神分裂癥患者伊潘立酮和代謝產(chǎn)物的穩(wěn)態(tài)血藥濃度。
[Abstract]:I. purpose 1) to study the pharmacokinetic characteristics of ipyridone and its metabolites in Chinese healthy volunteers. (2) to establish a group pharmacokinetic model of patients with schizophrenia treated with Ipperidone, to obtain the population pharmacokinetic parameters and to evaluate the influencing factors of the population parameters. To study the effect of CYP2D6 (10rs1065852) genotype on the plasma concentration and pharmacokinetic parameters of iperidone and its metabolites. II. Methodology 1) Sixteen Chinese healthy volunteers were selected according to the criteria of inclusion / exclusion, randomized, open, two doses of LMG 3 mg / g, double cycle fork test. The elution period is 14 days. The pharmacokinetic parameters were calculated by WinNolin software (SPSS 18.0) before and after the administration of the drug. The pharmacokinetic parameters were calculated by the software WinNolin, which was used to calculate the pharmacokinetic parameters of Ipperidone and its metabolite M _ (1) M _ (2) by the method of HPLC-MSMS for the determination of Ipantone and its metabolite M _ (1) / M _ (2) before and after the administration of the drug. The results were analyzed by SPSS 18.0 software. The pharmacokinetic parameters were analyzed by SPSS 18.0 software. (2) 70 schizophrenic patients were screened according to the inclusion / row criteria, and basic information was collected, and the 15th day after continuous administration (dose titration) was collected. The serum concentrations of Ipperidone and its metabolite were determined by HPLC-MS / MS method on the 28th day and 42 h after administration. SPSS 18.0 was used to analyze the data and to establish a colony pharmacokinetic model by NONMEM software. Blood samples were collected from 14 healthy volunteers and 70 schizophrenic patients. Peripheral lymphocyte DNA was extracted. The genotypes of CYP2D6 and 10rs1065852) were genotyped by SPSS 18.0 pairs. Correlation analysis of pharmacokinetic parameters was carried out. III. Results 1) after oral administration of Ipperidone tablets, the two compartment model (M 2) and the one compartment model (M 2) of Ipperidone M 1 were conformed to the two compartment model. The main pharmacokinetic parameters of Ipperidone were C _ max AUC _ (C) C / F, there was significant difference among individuals, the increase of AUC and Cmax was not dose-proportional, and the incidence of adverse reactions was higher in healthy volunteers after taking Ipperidone tablets. 2) the population pharmacokinetic model showed that, The introduction of variables can partly explain the effect of the mutation of different individuals: CYP2D6N10 on the elimination of rate constant K20) and the rate of M2 production by 1.8% and 7%, respectively, and the RBCs of erythrocyte number were introduced into the model. The individual difference in the volume V _ 2 of the distribution of Ipperidone decreased by 1.3%. (3) the frequency of CYP2D6*10 genotype in healthy volunteers and schizophrenia patients was 21.4% and 24.30.The corrected values of Ipperidone and M1 concentration / dose of CYP2D6*10TT carriers in schizophrenic patients were increased, but the corrected values of M2 were decreased. There was no significant difference in pharmacokinetic parameters among CYP2D6*10 genotypes in healthy volunteers. IV. Conclusions 1) the increase of pharmacokinetic parameters was not proportional to the dose of lmg and 3mg in Chinese healthy volunteers. Some pharmacokinetic parameters were higher than those reported abroad, the tolerance dose was low, and the incidence of adverse reactions was high. 2) the population pharmacokinetic model established in this study showed that CYP2D6*10 mutation and erythrocyte number could decrease the inter-individual variation of population parameters K20K24 and V2, and could partly explain the inter-individual variation of the clearance and distribution of Ipperidone. The genotype of CYP2D6 (10rs1065852) affects the steady-state plasma concentrations of Ipperidone and its metabolites in patients with schizophrenia.
【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R969

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