Dissertation > Medicine, health > Pharmacy > Pharmacology

The Study of Dipfluzine’s Pharmacokinetics

Author DongJiaLi
Tutor WangYongLi
School Hebei Medical University
Course Pharmacology
Keywords Dipfluzine HPLC Blood concentration Pharmacokinetic Distributed Excretion Plasma protein binding rate
Type Master's thesis
Year 2003
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Dipfluzine newly developed piperazine calcium antagonists, selective expansion of the basilar artery, vertebral arteries and coronary artery. And the high selectivity cerebrovascular stronger than cinnarizine. In addition it can reduce brain edema, increase cerebral blood flow and improve the symptoms of cerebral ischemia, reduced infarct size, and also has the role of anti-platelet aggregation and thrombus formation, significant protection of ischemic brain injury, most likely development a new drug for the treatment of ischemic cerebrovascular disease. Therefore necessary to explore the the drug metabolism dipfluzine kinetics, that further clinical studies provide experimental data. The experimental rats by the oral route of administration, the use of high performance liquid chromatography, the study dipfluzine pharmacokinetic characteristics in rats. The first part of the serum dipfluzine high performance liquid chromatography to establish its purpose of pharmacokinetic studies in rats: the establishment of dipfluzine (Dipfluzine, Dip) HPLC analysis method to study double benzene fluoride piperazine pharmacokinetic behavior in rats. Method: 1) high-performance liquid chromatography method (HPLC), using DIKMA (Dima) Diamond C18 column (250 × 4.6 mm, 5 μm), mobile phase of methanol - water (containing 0.01mol.L-1 tetrabutylammonium bromine ammonium) pH = 4.0, flow rate 0.8ml.min-1, UV detection wavelength was 254 nm, the internal standard for fluoride Gui Cinnarizine (Flu). 2) rat gavage dose of dipfluzine 40mg.kg-1 the orbital blood at different times after administration (15min, 30min, 1h, 2h, 4h, 8h, 12h, 24h). 3000r.min-1, 4 ℃, centrifugal 10min lt; WP = 5 gt; blood serum and internal standard, weak alkaline conditions, cyclohexane - isopropanol, hydrochloric acid solution, dichloro methane and other multi-step extraction, and evaporated to dryness. 3) record peak area, peak area ratio of dipfluzine and fluorine Gui Cinnarizine calculated plasma concentration, 3P97 pharmacokinetic software for automatic fitting process. Minimum to maximum theoretical plasma concentration values ??with the experimentally determined value of the correlation coefficient and AIC as a criterion to select the best-compartment model. Results: Determination of the plasma concentration of rats fed at different time points after administration dipfluzine. Serum dipfluzine linear in the range of 0.0625 ~ 4μg.ml-1 well, the regression equation was Y = 0.5049X-0.0008, r = 0.9999, the lowest detection concentration 5ng ml-1. High (0.3μg.ml-1), (0.75μg.ml-1), low (3μg.ml-1) three kinds of concentration average recovery was 102.1%, 99.7%, 101.0%, intra-day precision RSD values ??were 0.6%, 3.2%, 3.9%, inter-day precision RSD values ??were 0.4%, 3.9% and 4.1%, respectively. One-compartment open model the dynamic behavior of rats after oral administration. The kinetic parameters: A = 0.827 ug / ml, Ke = 0.1481 / h, Ka = 2.5931 / h, T LAG = 0.035h, t1 / 2 (Ka) = 0.267h, t1 / 2 (Ke) = 4.692h Tmax = 1.172h Cmax = 0.656 μg / ml, AUC = 5.277 (μg.ml) * h, CL = 7.581 L / Kg / h, V = 51.318 L / kg Conclusion: In this study, for the first time determined by HPLC rats the serum dipfluzine concentration. This method is highly sensitive, selective line plasma concentration requirements. The research results show that the gavage dipfluzine in rats rapidly absorbed with peak plasma concentration reached in about 1 hour. The Second part dipfluzine, tissue distribution in rats, excretion and plasma protein binding rate Objective: To study dipfluzine in rats in vivo tissue distribution, excretion, etc. lt; WP = gt; dynamic change law and the characteristics of the pre-clinical pharmacokinetic study. Method: 1) rats to dipfluzine 40mg.kg-1 dose gavage were decapitated at different times after administration (1h, 6h, 24h), heart, liver, spleen, lung, kidney, brain , pancreas, fat, skeletal muscle, and other tissues. Taken the organizations weighed, homogenized, and the supernatant was added internal standard after multi-step extraction of cyclohexane - ethyl acetate, hydrochloric acid solution, and evaporated to dryness. 2) rats to dipfluzine 40mg.kg-1 dose orally, anesthesia, do bile duct intubation, drainage of bile, collected at different times (1h, 6h, 12h, 24h) bile. Taken bile cyclohexane - isopropanol extract, and evaporated to dryness. 3) rats dipfluzine, after gavage 40mg.kg-1 dose placed in metabolic cages to collect urine and feces. Feces weighed homogenate. Of stool supernatant urine treatment with bile. 4) measured by equilibrium dialysis, high (0.5μg.ml-1) (1μg.ml-1), low (2μg.ml-1) different the concentration dipfluzine the plasma protein binding rate. 5) high-performance liquid chromatography, using DIKMA (Dima Company) Diamond C18 column (250 × 4.6 mm, 5 μm), a mobile phase of acetonitrile - water (including 0.01mol.L-1 tetrabutylammonium bromide) pH = 4.0, flow rate 0.8ml.min-1, the detection wavelength was 254 nm, the internal standard flunarizine. Recording the peak area of ??each sample was calculated drug concentration. Results: 1) in rat tissues dipfluzine 0.0125-1.6 μg.ml-1 linearly. Dipfluzine are distributed in the determination of the organization, which is more to the liver, lung, kidney, and brain tissue. 2) bile, urine, and feces dipfluzine 0.05-1.6 μg.ml-1 and 1-64 μg.ml-1 of linearity in the range a good relationship. The excretion of urine dipfluzine total of 0.1% of the dose gavage; the feces dipfluzine excretion of total 8.29% of the dose gavage; bile excretion less, only 0.01%. 3) high concentration and in the concentration dipfluzine the plasma protein binding rate is basically the same, respectively, 68.4% and lt; WP = gt; 69.4%, but the low concentration dipfluzine plasma protein binding rate higher to 94.4 %. Conclusion: dipfluzine widely distributed in rats, in higher concentrations in the liver, lung, brain tissue. Drugs mainly from feces, urine excretion in the bile excretion is very low. The high concentration and the concentration dipfluzine plasma protein binding rate is basically the same, but the low concentration dipfluzine of plasma protein binding rate is higher.

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