【作者】 黄晓晖；

【导师】 李俊； 孙瑞元；

【作者基本信息】 安徽医科大学 ， 药理学， 2005， 博士

【摘要】 血管紧张素Ⅱ受体（AT₁）拮抗药的药动学—药效学结合模型研究 血管紧张素Ⅱ（AT₁）受体拮抗剂选择性拮抗AT₁,抑制血管紧张素Ⅱ介导的血管收缩,间接促进醛固酮的释放,并能间接引起肾素、血管紧张素Ⅱ的升高,临床广泛用于治疗高血压及充血性心力衰竭等。厄贝沙坦为新型的非肽类血管紧张素Ⅱ受体AT₁的拮抗药,降压效果好,不良反应少,且有保护靶器官作用。利尿剂与血管紧张素Ⅱ受体拮抗剂药物联用是一种临床常用治疗方法。目前在血管紧张素Ⅱ（AT₁）受体拮抗剂研究领域,尚有些有待解决的基础和临床问题,如药效滞后、剂量问题、作用机制和副作用机制等。另一方面,药动学—药效学结合模型（PK-PD modeling）将药动学与药效学相联系,定量阐明给予一定剂量后所引起的药理作用的时间过程,有助于药物个体差异分析,作用机理探讨、临床给药方案制定、疗效和安全性评估、临床试验模拟等研究工作,近年来在药理学、毒理学、临床应用及新药开发等领域发挥越来越重要的作用。 目前国内外药动学—药效学结合模型应用于血管紧张素受体拮抗剂及高血压联合用药的研究尚未见报道。本课题运用药动学—药效学结合模型理论,从时间、血药浓度、药物效应及联用效应等多维角度进行探索,分析血管紧张素Ⅱ（AT₁）受体拮抗剂厄贝沙坦及其与利尿剂氢氯噻嗪联用在健康志愿者、肾性高血压大鼠及肾性高血压犬体内的实验数据,建立数学模型,弄清剂量、药物浓度、药物效应及时间之间的关系,可估算预测药物效应的时间过程,提供有价值的药动学及药效学参数,从而有助于临床合理用药。本研究主要分为如下几部分: 1.药动学—药效学结合模型的定量分析方法研究 本课题首先需建立药动学—药效学结合模型的定量分析方法。药动学—药效学结合模型种类繁多,内容丰富。本课题涉及的药动学—药效学结合模型定量研究方法如下:药动学—药效学结合模型的药动学模型部分采用房室模型。药效学模更多还原

【Abstract】 Irbesartan is a non-peptide long lasting competitive antagonist of AT1-type angiotensin II receptor. Hydrochlorothiazide(HCTZ) is a well-known thiazide diuretic, widely used as antihypertensive agent that increases sodium, chloride, water and potassium excretion and secondary activation of the Rennin-Angiotensin System. Combined administration of the two drugs is often recommended for antihypertensive therapy, especially when monotherapy is not effective. Previous studies have shown that there was great individual difference after oral administration of the two drugs. Quantitative study of pharmacokinetic and pharmacodynamic of irbesartan are still lacking. Individual therapy should be offered, which needs more precise pharmacokinetic and pharmacodynamic parameters. On the other hand, the importance of PK/PD modeling approaches is widely appreciated in drug research. But there are few reports on its application of combined drug administration and comparative studies between single-dose and multi-dose situations. The objective of the present study therefore was to explore the experimental effect-concentration data and investigate the pharmacokinetic and pharmacodynamic of irbesartan and its with HCTZ in healthy volunteers, renal hypertensive rats or dogs using PK/PD model. Thereby, It can provide a more rational basis for patient-specific dosage individualization and may thus guide applied pharmacotherapy to a higher level of performance.1. Quantitative method of pharmacokinetic-pharmacodynamic modelingFirst of all, we need to eatablish appropriate quantitative method of pharmacokinetic-pharmacodynamic modeling. There are many kinds of quantitative methods of PK-PDmodeling. The methods used in our study was as follows: The pharmacokinetic model component provides the concentration-time course in the sampled body fluid, resulting from the administration dose. Compartmental pharmacokinetic models were adopted in the study for this purpose. The pharmacodynamic model component relates the concentration provided by the kinetic model to the observed effect. Dependent on the mechanisms involved, it may consist of one or several transduction and response elements that express the finally observed effect directly or via multiple intermediary response steps. The most commonly used pharmacodynamic model used in our study were sigmoid Emax model. We used sheiner effect compartment model to solve the hysteresis loops problem. AIC, SUM and r2 and other statistical methods were used as modeling checking. Simplex method was used as the main computational Method in our study.2. High-performance liquid chromatographic analysis of irbesartan in plasmaThe Waters HPLC system consisted of a 1525 binary HPLC pump, a 717plus Autosampler, a column incubator, a 2487 dual X absorbance detector, a 2487 Multi I Fluorescence Detector and Breeze Software. Chromatography of Irbesartan: A Nova-Pak C18(150x3.9mm, 4um) column was used for analysis. The fluorescence detector was set at an excitation wavelength of 250nm and emission wavelength of 371nm. The mobile phase was acetonitrile:water (40:60), adding phosphoric acid and adjusted pH to 3.5. The flow rate was lml/min. The precision of the method was defined from the validation experimental data by a between-day coefficient of variation of 8.83%. The detection limit was lOng/ml. The standard curve showed good linearity for irbesatan concentrations ranged from 20 to 5000ng/ml, and the coefficient of correlation was 0.9993. Sample preparation of Irbesartan: 500ul dog plasma was used for extraction. Plasma samples were slowly added into the solid-phase cartridge (HLB lcc,OasisTM, Waters, USA), which had been previously activated with 2ml methanoland balanced with 2ml 0.1% phosphoric acid. After the sample had been absorbed by the cartridge, the cartridge was washed with 2ml 0.1% phosphoric acid, and the irbestan was then eluted with methanol: 0.1% phosphoric acid (50:50, v/v). After centrifugation at 15000 rpm/min for 15 min, lOOul supernatant was drawn and lOul injected into the HPLC.3. The pharmacokinetics of irbesartan in healthy Chinese volunteers.The pharmacokinetics of irbesartan were studied in 18 healthy volunteers. A single oral dose 300mg irbesartan of drugs were given to each volunteer. The concentrations in plasma were determined by HPLC method. The main pharmacokinetic parameters of irbesartan were 0.080±0.027h"!, TI/2 10.277i4.484h"1, MRT 4.797±0.999h, Cmax 2.506±0.655ug/mL,Tmax 1.5±0.70h, CL/F 31.603±6.475L/h , AUC0 - 24 9.986± 2.237|ig-h/mL, AUC0-ool0.962±3.243ugh/mL. The result of the study also show the great individual difference, the range of Cmax, W a°d AUCo-24 were 1.47~4.04mg ? L~ \ 0.75~3h, AUCo-24 6.63~14.02mg *h ?L~I. The result showe that we shoud pay more attention to individual therapy .4. Pharmacokinetic-pharmacodynamic modeling of irbesartan in healthy Chinese volunteersThe purpose of this study was to establish the combined pharmacokinetic-pharmacodynamic modeling of Irbesartan in healthy Chinese volunteers and provide valuable PK/PD parameters for clinical dosage individualization. Ten healthy Chinese male volunteers received 300mg irbesartan tablets orally. Plasma drug concentration was determined by HPLC method and Pharmacologic effects, including SBP and DBP, were measured simultaneously. The experimental data were quantitatively analyzed according to the PK-PD model theory. Pharmacokinetic and pharmacodynamic parameters were calculated. The pharmacokinetic profiles of irbesartan conformed to atwo-compartment open model. There were hysteresis loops between effects and plasma concentrations. The relationship between effects and effect compartment concentrations (Ce) could be represented by the sigmoid-Emax model. The Emax values of inhibitory effects on SBP and DBP of irbesartan were (14.8±1.5) and (9.8±2.1) mmHg, EC50 were (0.29±0.11) and (0.18±0.07) ug-mL"’, K?, were (0.62±0.09) and (0.68±0.07) h ’* respectively. The PK-PD model of irbesartan was successfully eatablished in healthy volunteers. These findings may provide a more rational basis for patient-specific dosage individualization.5. Pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide in renal hypertensive ratsThe study was to characterize the pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide(HCTZ) in renal hypertensive rats at non-steady-state and steady-state using PK-PD modeling. Renal hypertensive rats received repeated oral administration of irbesartan(30mgkg~’) either alone or in combination with oral administration of HCTZ(7.5mgkg~’) for 8 days. A control group received only the repeated oral administration of HCTZ(7.5mg-kg ~l). Plasma concentrations were determined by HPLC method. Systolic Blood Pressure(SBP) and Diastolic Blood Pressure(DBP) were checked simultaneously as measures of antihypertensive effects at scheduled time points on the first and the 8th day after dosing. The pharmacokinetic and pharmacodynamic parameters were calculated and quantitatively analyzed according to the PK/PD model theory. The pharmacokinetic profile of irbesartan conformed to a two-compartment open model. The concentration-time course of irbesartan was not altered by HCTZ, whereas irbesartan increased the peak plasma concentration and area under the concentration-time curve (AUC) of HCTZ at steady-state. HCTZ has almost no antihypertensive effects in hypertensive rats at non-steady-state. The blood pressure-lowering effects of irbesartan/HCTZcombinations were better than that of irbesartan alone. HCTZ can increase drug actions of irbesartan. There were hysteresis loops between effect and plasma concentration of irbesartan after single dosing. However, hysteresis loops disappeared at steady-state with more rapid attainment of maximum concentration and effects. The relationship between effects and effect-compartment concentration of drugs were represented by the sigmoid Emax model. There is a synergistic pharmacodynamic interaction between irbesartan and HCTZ in hypertensive rats. There are some difference of pharmacokinetic and pharmacodynamic properties between irbesartan and irbesartan/HCTZ combinations at non-steady-state and steady-state in renal hypertensive rats.6. Pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide in renal hypertensive dogsThe study was to characterize the pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide(HCTZ) in renal hypertensive dogs at non-steady-state and steady-state using PK-PD modeling. Renal hypertensive dogs received repeated oral administration of irbesartan(30mgkg~’) either alone or in combination with oral administration of HCTZOOmgkg"1) for 8 days. A control group received only the repeated oral administration of HCTZ(10mg-kg ~ l). Plasma concentrations were determined by HPLC method. Systolic Blood Pressure(SBP), Diastolic Blood Pressure(DBP), dp/dtmax, LVSP, AT II, ALD and ET were checked simultaneously as measures of antihypertensive effects at scheduled time points on the first and the 8th day after dosing. The pharmacokinetic and pharmacodynamic parameters were calculated and quantitatively analyzed according to the PK/PD model theory. The pharmacokinetic profile of irbesartan conformed to a two-compartment open model. The concentration-time course of irbesartan was not altered by HCTZ, but irbesartan increased the peak plasma concentration and area under the更多还原