الفهرس 
INTRODUCTION
INTRODUCTION ON 1.4 DIHYDROPYRIDINESOnly 14 pages are availabe for public view
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Abstract
1,4-DihyDROPyridine compounds are used mainly for the treatment of hypertension and angina through inhibition of the entry of the calcium ion to the cells. The electrochemical study of these compounds is important to investigate their mechanism of action, stability and metabolism. This study was performed on five compounds of this group namely; barnidipine HCl, benidipine HCl, nicradipine HCl, nifedipine and isradipine. Firstly the study involved the elucidation of the mechanism of the electrochemical reaction of these compounds on glassy carbon electrode using different techniques; cyclic voltammetry, controlled potential electrolysis and spectroelectrochemistry. This study showed that these compounds have two electrochemicaly active centers, 1,4-dihyDROPyridine and nitrophenyl group in compounds I-IV or 2,1,3-benzooxodiazole in isradipine. The mechanism of the electrochemistry of these compounds on surface of glassy carbon electrode was suggested. The adsorption of these compounds on surface of gold and glassy carbon electrodes was studied by specular reflection technique. This study showed that adsorption of these compounds on surface of glassy carbon is less than that on surface of gold electrode and this indicates the validity of glassy carbon electrode for electrochemical detection in HPLC. Adsorption of these compounds on surface of gold electrode decreases by increase in pH. At alkaline pH there is no adsorption. Isradipine and nifedipine do not adsorb on surface of gold electrode at any pH and this indicates that adsorption of other studied compounds is due to the HCl salt. On surface of glassy carbon there is no adsorption at acidic or alkaline pH, while at neutral pH all compounds showed little adsorption.
Quantitative study of these compounds was performed by HPLC technique using electrochemical detector in alkaline mobil phase (pH 11.8) on alumina column. The chromatographic conditions were optimized for each compound. Photostability of these compounds, in acetonitrile, to fluorescent and room light, sun light and UV light at 365nm was estimated by HPLC method and it was found that all compounds are approximatly stable to fluorescent and room light up to 5h., while sun and UV lights
cause their rapid degradation. Isradipine ,due to its unique structure, was found to be the most stable one. Effect of heat on the stability of these drugs in acetonitrile was studied at three temperature levels (40, 60 and 80 °C) and it was found that all compounds are stable at all temperature levels.
The HPLC/ECD method was applied for the determination of the drugs in pure form and in biological fluids (serum and plasma). In pure form the calibration range was from 3xlO”8; 5xlO~5M for barnidipine HC1, lxlO”8: 5xlO”5M for benidipine HC1 and \x\0^ :3xlO”5M for both nicradipine HC1 and isradipine with the correlation coefficients ranging from 0.9988 to 0.9998. In human serum the method is sensitive to detect lng/ml of each of barnidipine HC1, benidipine HC1 and nicradipine HC1 and 0.5ng/ml of isradipine using 0.5ml of serum. The calibration range in serum was 5:500ng/ml with C.C. 0.9980 for barnidipine HC1, 5:200 ng/ml with C.C. 0.9958 and 0.9997 for benidipine HC1 and nicradipine HC1 respectively. For isradipine calibration from 2:200 ng/ml with C.C, equal to 0.9922.
Interference from other calcium antagonists or co-adminatared drugs was studied on 25 compounds and was found that all studied compounds did not cause interference except of barnidipine HC1 and nicradipine HC1 which have the same retention time.
The proposed HPLC/ECD method was applied for pharmacokinetic study of barnidipine HC1 after its oral administration to dogs. Pharmacokinetic data were obtained by analysis using a one compartment model with a first order elimination rate constant. These data demonstrate that this compound is rapidly absorbed and eliminated by the dog. By this method, barnidipine can be accurately determined for bioavilability studies.