| Haloperidol (Hal) is an antipsychotic agent. Our previous research showed that Hal could noncompetitively antagonize the contraction of coronary artery induced by phencyclidine, agonists of opioid receptor, and noradrenaline, etc. However, it was not used as an anti-myocardial ischemia drug due to its extrapyramidal adverse reactions. In consideration of this, we synthesized a series of quaternary ammonium salt derivations of Hal .One of these compounds with serial number F2 (N-n-butyl haloperidol iodide) was screened. F2 has the structure of quaternary ammonium salt that has high polarity and low lipophilia. This made it impossible to pass through blood-brain barrier and diffuse into brain, so the central nerve reaction might be avoided, at the same time, it was kept the obvious effect of dilating coronary artery. The pharmacodynamics study demonstrated that F2 possessed strongcardiovascular activity. What's more, the mechanism was definite, which revealed a better development prospect. This paper is to study synthesis, separation, purification, determination of content of F2 and pharmacokinetics profile of F2 in rabbits. The three parts of paper are as follows:1. Synthesis, Separation and Purification of F2F2 were synthesized through the following process. Hal was dissolved in chloroform and reacted with n-butyl iodide in reflux condition. Then the reaction substance was recrystallized. The recrystallized substance was not pure. Then we discovered that there was a peak of impurity by HPLC which had more retention time than that of F2 and wasn't deleted easily with recrystallization. This experiment separates successfully to get the high degree of pure F2 with the column chromatography method.2. Determination of F2 by HPLCTo establish HPLC method for the determination of F2. The separation was performed on a phenomenex Luna 5 m C18 column (4.6mm X 250mm) with CH3CN-CH3OH-0.025mol/L KH2PO4=45:5:50(v/v) as the mobile phase, the flow rate was 0.8ml/min, the detection was set at 248nm and the column temperature was maintained at 35 C. Results: the calibration curve was linear in the concentration range of l~10ug/ml, r=0.9992. The method is simple, rapid,accurate and reproducible. It may be adopted for quality control of thisdrug.3 Pharmacokinetics of F2 in rabbitsIn order to give a gist for instruction about dose of animal's experiment and decision about drug project of clinical trial. This paper is to study pharmacokinetics profile of F2 in rabbits by HPLC-MS technique. The result shows that an open two-compartment model best described the concentration-time profiles for F2. The major Pharmacokinetics parameters were followed respectively:The half-life of distribution Phase: T1/2 a =0.096 hours, the half-life of elimination phase: T|/2 P =6.42 hours, the volume of the central compartment Vc=3.71L, the total areas under the concentration-time curve AUC=182.79 ng /(ml h), the plasma clearance CL=12.87L/h. The concentration-time equation is C=619.79 e -11.36t+9.37 e -0.116t.HPLC-MS method that was used to detect the plasma concentration of F2 was shown to be sensitive, specific. The characters of F2 are quick distribution and low concentration during distribution phase. Pharmacokinetics of F2 belongs to the first order kinetics.
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