Study On The Pharmacokinetics Of Telmisartan In Normal Chinese Volunteers

Objective: Telmisartan is a new-type of angiotensin receptor blockers characterized by high-efficiency with a long duration and less-toxicity. It inhibits irreversibly the AT1 receptor of angiotensin II with a high specificity, and does not influence other receptors including those that regulate cardiovascular system. Therefore, telmisartan shows exact and steady effects on primary hypertension in lowering blood pressure effectively during the time of 24 hours in the whole day and also at the morning peak period, reducing the occurrence of cardiovascular and cerebral vascular attack. Moreover, telmisartan also plays an excellent role in protecting ischemic myocardium and kidney, reversing the cardiovascular re-modeling, improving the diastolic function of the left ventricle and reducing insulin resistance, etc. In brief, the less side effects and high tolerance of telmisartan endow itself a better value in clinical application, therefore, it is suitable to the patients who do not tolerate other anti-hypertension measures in particular.The blood concentration of telmisartan is relatively lower and difficult to be detected in biological specimen. The authors referred to the literature internationally and chose the method of high performance liquid chromatogram (HPLC) to study the pharmacokinetics of telmisartan in normal Chinese volunteer in order to provide important data for clinical application. The pharmacokinetics of telmisartan in normal Chinese volunteers was investigated by using telmisartan tablets from Xiamen Mchem Pharmaceuticals Co., Ltd.(T1) ,from Fuzhou Neptunus Futao Pharmaceuticals Co.,Ltd. (T2) and T from Germany Boehringer Ingelheim Co., Ltd. for this study.Methods: 1 Test protocolVolunteers underwent physical examination before the trial, and those with normalfunctions of heart, liver and kidney entered the trial. The selected volunteers also have no history of heart, liver and kidney diseases, no history of drug allergy and no habit of smoking and drinking. 2 weeks before the trial and during trial, the selected volunteers did not use any drugs else and were prohibited against smoking and alcoholic drinks, in addition, they were also full of vigour. 18 selected volunteers were randomly divided into 3 groups and kept in fast from 8:00 pm the day before the trial, on the trial day, 80 mg oftelmisartan control preparation--T and two trial preparations-- T1 and T2 wereadministrated orally to the 3 groups respectively with 200 ml of warm boiling water in each volunteer. 4 hours later, food containing low fat and protein were given (no difference among the 3 groups). 3 ml of venous blood sample was collected with heparin against coagulation before telmisartan administration and at the time of 0.17,0.33,0.67,1,1.5,2,3, 4, 6, 8, 12, 24, 48 and 72 hours after the administration respectively, plasma was extracted by 10-minite centrifugation and kept at -30 ℃.2 Determination of telmisartan concentrations in plasmaThe total of 10 μl (320μg·ml-1) of α-naphthol was added into 0.4 ml of plasma, which was stirred thoroughly for 0.5 min, then added 0.4 ml of acetaldehyde and stirred for 5 min, and centriiuged at 4000 rpm for 20 min. Total 20 μl of the supernatant was analyzed to determine telmisartan concentrations in different interval by using HPLC. Chromatographic condition was described as below: column: from Dalian Whether Hypersil C18 column (4.6×250 mm) , mobile phase: acetonitrile, 0.02mol·L-1 potassium dihydrogen phosphate (diethylamine phosphate pH 5.8) =45 : 55 (v/v) ,flow rate: 1.0ml·min-1. the fluorescence detection wavelengths were λ ex 305nm and s em 365nm. -Tem: 20 ℃. The recovery rate and accuracy were both evaluated.3 Statistical methodsData were analyzed with 3P97 pharmacokinetic software, the compartment model was determined according to F-test and AIC value, while the weight was selected by the goodness of fit, area under the curve (AUC) was calculated by keystoning method, peak concentration (Cmax) and time for peak concentration (Tmax) were taken from the survey. Analysis of variance and two-sided one-way t test were performed on AUC10 , AUC∞0, Cmax, Tmax of telmisartan control preparation~T and two trial preparations~T1 and T2 in order to determine the bioequivalence between T1, T2 and T.ResultsTelmisartan presented a high chromatographic peak, which was separated nicely from the inner control, and no interfering peak existed. The Retention time of telmisartan and theinner control was 5.51 min and 9.91 min respectively, while the regression equation was C=76.3077R+0.0316 (r=0.9999), the linear range of telmisartan concentration was 2~1024 ng·ml-1. The minimum detectable concentration of tehnisartan in plasma was 1ng·ml-1, the recovery rate, the within-day RSD and the between-day RSD all accorded with the requests of biologic sample analysis. It is indicated that the method used in the study is specific, accurate and reliable.The results showed that the pharmacokinetics of tehnisartan in normal Chinese volunteers belongs to the 2-compartment open model, the main pharmacokinetic parameters of the inner control and the two detected tablets (T1 and T2) were as follows: Cmax was 931.01±367.66ng·ml-1, 854.48±338.56ng·ml-1 and 894.15±421.70ng·ml-1 respectively. Tmax was 0.97±0.63 h, 1.29±0.69 h and 1.44±0.77 h separately; T1/2α was 1.88±1.73 h, 1.79±1.19 h and 2.96±3.291.19 h; T1/2β was 28.14±14.09 h, 26,25±9,68 h and 26.97±10.78h, AUC0(?) was 4085±2313 ng·h·ml-1, 3826±1922 ng·h·ml-1 and 3920±2199ng·h·ml-1 s AUC0- was 4751±2742 ng·h·ml-1, 4159±2192 ng·h·ml-1 and 4352±2569 ng·h·ml-1. From the results above, the main pharmacokinetic parameters between the inner control and the two detected tablets (T1 and T2) are similar, compared to the inner control, the relative bioavailability of the two detected tablets (T1 and T2) was F0(?) (99.53±24.05)% and (97.51±15.64)%; F0- (98.20±27.64)% and (96.51±15.80)%. Analysis of variance, 2-lateral and 1-lateral off-test of AUC0(?), AUC0- and Cmax proved that the bioequivaience exists between the two detected tablets (T1 and T2) and the inher control.Conclusions1 The main pharmacokinetic parameters between the inner control and the two detected tablets (T1 and T2) in normal Chinese volunteers are similar.2 The bioequivaience exists between the two detected domestic tablets (T1 and T2) and the imported inner control tablet.