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Int. J. Chem. Sci.: 8(4), 2010, 2808-2814 COMPARATIVE BIOAVAILABILITY OF TWO LISINOPRIL FORMULATIONS AFTER SINGLE DOSE ADMINISTRATION TO HEALTHY VOLUNTEERS NAGHAM A. JASIMa, ADLA A. SALOMI* and FADHIL M. ABIDa a College of Medicine, Babylon University, IRAQ Ministry of Science, and Technology, Baghdad, IRAQ ABSTRACT Two formulations of lisinopril (5 mg) were evaluated for bioequivalence after single dosing to 20 healthy volunteers. The study was conducted according to an open, randomized, 2-period crossover design with a 1-week washout interval between doses. The concentrations of lisinopril were determined in plasma at different times by HPLC method. The pharmacokinetic parameters AUC (0-36 hr)), Cmax, Tmax and t ½ were calculated and tested for bioequivalence after logarithmic transformation of data and ratios of tmax were evaluated non-parametrically. The analysis of pharmacokinetic data revealed the following test/reference ratios and their confident interval (90% CI): 0.887 (0.84-1.22) for AUC (0-36 hr), 0.95 (0.83-1.25) for Cmax and 1.0 (0.99-1.08) for the 90% CI for tmax was 0.94-1.07. All parameters showed bioequivalence between both formulations (Samapril and Zestril). A discrete fall in both; systolic blood pressure (SBP) and diastolic (DBP) blood pressure was observed after drug administration. The time course of both the parameters was similar for the 2 formulations. Key words: Bioavailability, Lisinopril, Angiotensin, HPLC. INTRODUCTION Lisinopril is an oral long-acting angiotensin converting enzyme inhibitor1,2. It is a synthetic peptide derivative and is chemically described as (S)-1-[N2-(1-carboxy-3phenylpropyl)-L-lysyl]-L-proline dihydrate. Its empirical formula is C21H31N3O5.2H2O. It is a white to off-white, crystalline powder, with a molecular weight of 441.53. It is soluble in water and sparingly soluble in methanol and practically insoluble in ethanol. It inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone ________________________________________ * Author for correspondence; 2809 Int. J. Chem. Sci.: 8(4), 2010 secretion by the adrenal cortex. The beneficial effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decrease aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 meq/L; however, approximately 15% of patients had increases greater than 0.5 meq/L and approximately 6% had a decrease greater than 0.5 meq/L. Removal of angiotensin II. Negative feedback on rennin secretion leads to increased plasma renin activity. The mechanism through, which lisinopril lowers blood pressure, is believed to be primarily suppression of the renin-angiotensin-aldosterone system, so lisinopril is antihypertensive even in patients with low-renin hypertension1,2. When lisinopril is used in pregnancy during the second and third trimesters, AEC inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, lisinopril should be discontinued as soon as possible3. EXPERIMENTAL Materials and methods Samapril 5 mg tablet as test drug was obtained from SDI, Sammera, and Zestril 5 mg tablet was obtained from commercial market. Study program Twenty healthy, nonsmoking, male volunteers (mean age ± SD, 28.5 ± 4.94 years; weight, 66.9 ± 8.59 kg; height, 168.5 ± 4.11 cm) in two groups took part in this study. All volunteers gave written informed consent after they had received detailed instructions about the study performance of the drug. All volunteers were in good physical health according to physical examination, hematological and urinary laboratory tests. Subjects did not take any other medications for at least 1 week prior to and throughout the study. Each subject fasted overnight before the experiment. Tablets were swallowed with 150 mL water. A light, normal lunch consisting of cheese, bread, tea, and water was given to all subjects 4 hours after dosing. A washout period of 1 week was included between the administrations of each product. In the second phase, the test and reference tablets were crossed between the two groups of volunteers. Blood sampling The blood samples had been drawn from each volunteer after oral dose administration 2810 N. A. Jasim et al.: Comparative Bioavailability of…. of 5 mg of test and reference drug, according to the randomization schedule, with 150 mL drinking water. Blood samples (2 mL) were taken via an indwelling venous cannula at the following times: before drug administration (0 hr), and 1, 2, 4, 7, 9, 12, 15, 18, 24 and 36 hr after drug administration. Within 10 minutes of collection, blood samples were centrifuged at 3000 rpm for 10 min and after clot retraction from each sample, two aliquots of plasma were transferred to labeled tubes. All samples were handled at room temperature before storage at –20ºC until assays were performed. High-performance liquid chromatographic (HPLC) analysis Analysis was performed on Shimadzu liquid chromatograph model LC-10AVP, using a normal phase high-performance liquid chromatographic (HPLC) method described previously4. To 1 mL plasma in a 5-mL glass tube, 20 μL NaOH 1M and 20 μL 2-bromo 2acetonaphtone 0.02% solution in acetone were added. The mixture was left for 30 min. After adding 20 μL phosphoric acid 20% and 1 mL acetonitrile and also mixing for 5 min, the samples were centrifuged for 10 min and 500 μL aliquots were evaporated to dryness under nitrogen. The residue was reconstituted in 150 μL acetonitrile and 100 μL was injected onto the HPLC column (Supelcosil-NH2, 5 μm, 250 mm × 4.6 mm ID; USA). The mobile phase was acetonitrile: 0.25 mM potassium phosphate (33 : 67 v/v). Detection was carried out at Shimadzu 10Av detector set at 245 nm. The analytical method was fully validated in terms of intra- and inter-day variations, accuracy, and percent recovery according to USP guidelines3. The method was linear over a range of 25-800 ng/mL of drug in plasmas. The coefficients of variation between-day was determined from quality control samples processed together with each batch of samples. There were between 4.5% and 7.6% for concentrations ranging between 20 ng/mL and 500 ng/mL and the accuracy was between 96– 102%. The limit of quantification was found to be 20 ng/mL on the basis of signal-to-noise ratio. Pharmacokinetics and metabolism Following oral administration of lisinopril, peak serum concentrations of lisinopril occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose4-7. Lisinopril does not appear to be bound to other serum proteins. Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. The mean extent of absorption of lisinopril is approximately 25%, with large intersubject variability (6-60%) at 2811 Int. J. Chem. Sci.: 8(4), 2010 all doses tested (5-80 mg). Lisinopril absorption is not influenced by the presence of food in the gastrointestinal tract. The absolute bioavailability of lisinopril is reduced to 16% in patients with stable NYHA Class II-IV congestive heart failure8,9, and the volume of distributions appears to be slightly smaller than that in normal subjects. The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in healthy volunteers10. Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only, when the glomerular filtration rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment; however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher blood levels and area under the plasma concentration time (AUC) than younger patients. Lisinopril can be removed by hemodialysis11,12. To compare the rate and extent of absorption of lisinopril in both formulations, the following pharmacokinetic variables were calculated for each volunteer and product, using actual blood sampling times. The areas under the plasma concentration-time curves (AUC 036 hr) were calculated using the linear trapezoidal rule. The maximum plasma concentration (Cmax) and time to reach maximum plasma concentration (Tmax) were obtained directly from the plasma-concentration data. The elimination rate constant was calculated by least-squares regression using the last points of each curve. The pharmacokinetics parameter for test and reference drugs are summarized in Table 1. Table 1: Pharmacokinetic data of Samapril and Zestril 5 mg tablet; (n = 20) Zestril (reference) Samapril (test) Variables Unit Mean RSD % Mean RSD % Cmax ng/mL 170.33 4.029 162.1 7.15 Tmax hr 7 AUC0-36 ng.hr/mL 3372.8 83.74 2994.1 369.67 Ke hr-1 17.902 2.198 17.407 2.836 * RSD relative standard deviation 7 2812 N. A. Jasim et al.: Comparative Bioavailability of…. Statistical analysis The test and reference treatments in each study were compared with respect to relevant pharmacokinetic variables using analysis of variance with volunteer, product and period effects after a logarithmic transformation of the data. Point estimates and 90% confidence intervals (CI) for the test/reference mean ratios of these variables were calculated. Bioequivalence of the test and reference drugs was assessed on the basis of these CI, in relation to the conventional bioequivalence range of 80 – 125%. RESULTS AND DISCUSSION The concentration of lisinopril in blood serum of the volunteers with various time from 0-36 hr were measured by HPLC and the data were presented in Table 2, while the pharmacokinetics parameters are tabulated in Table 3. The summaries of both pharmacokinetic variables for test and reference drugs are given in Table 1. The mean plasma lisinopril concentrations-time profile for both formulations and comparison between them are constructed as shown in Fig. 1. 180 Zestril Samapril 160 Concentration (ng/L) 140 120 100 80 60 40 20 0 0 5 10 15 20 25 Time (hr) 30 35 40 Fig. 1: Comparison of mean concentration-time profile of test drug Samapril and reference drug Zestril 2813 Int. J. Chem. Sci.: 8(4), 2010 The 90% CIs for the test/reference mean ratios of the plasma lisinopril pharmacokinetic variables Cmax, AUC0-t and Tmax (as measures of the rate and extent of absorption of lisinopril, respectively), all fell within the conventional bioequivalence range of 80 – 125%. The test products (Samapril) are therefore bioequivalent to the reference product (Zestril) with respect to the rate and the extent of absorption. In conclusion, the results of this study showed that Samapril tablets manufactured in SDI are comparable to Zestril brands and can produce acceptable plasma concentrations. Table 2: Concentration of lisinopril in serum (ng/mL) with time after oral administration of 5 mg lisnoapril for 20 healthy volunteers (i) Samapril 5 mg tablet hr No. of subject 0 1 2 4 7 9 12 15 18 24 36 Mean 0 20.52 46.285 92.591 162.1 132.4 114.4 99.3 83.89 59.865 37.84 ± SD 0 2.388 9.435 9.525 9.40 9.653 10.921 11.19 3.591 6.448 7.159 (ii) Zestril 5 mg tablet Mean 0 25.5 47.39 ± SD 0 4.469 4.931 97.9 170.33 148.9 131.4 118.9 101.4 80.4 64.4 4.806 3.304 3.423 2.941 4.954 8.44 4.029 2.711 Table 3: Pharmacokinetics parameter of both lisinopril 5 mg tablet (i) Samapril 5 mg tablet Subject No. Ka Ka 0.5t Kelem. Kelem 0.5t Cmax Tmax AUC Mean 0.487 1.428 0.041 17.407 7 162.1 2944.14 ± SD 0.031 0.090 0.006 2.836 0 7.159 369.678 (ii) Zestril 5 mg tablet Mean 0.458 1.529 0.039 17.902 7 170.33 3372.8 ± SD 0.046 0.155 0.004 2.198 0 4.029 83.740 2814 N. A. Jasim et al.: Comparative Bioavailability of…. REFERENCES 1. K. Parfitt and W. Martindale, Pharmaceutical Press, 836 (1999). 2. S. H. 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