| 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...
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