The Pharmacokinetic Studies Of F0911 In BEAGLE Dog Plasma

Obesity is a common and frequently-occurring disease now, because of the improvement of human life. The duration of obesity is so long and the complications is so much, that it has become a great burden on patients and on the society. Obesity is a systemic disease, influenced by the Complex environment,which can be induced by many factors, and there are variety of complications.As a result, the treatment of obesity is difficult. In the early time of obesity, it's beter to contrl it by lifestyle changes like diet and increasing exercise. But when the patient's body mass index (BMI value) grew to 25 or 30 above, the proposed medical treatment is needed. Till now, the kinds of anti-obesity drugs are limited, and with great side effects. So the efficacy and safety anti-obesity drugs are not satisfactory. Such as orlistat and sibutramine ,they both have some effect on weight loss, but there are large number of adverse reactions reported, and there are only a few countries accept the two drugs Temporarily befor better anti-abesity drugs coming out. As a results,the development of anti-abesity drugs which has high efficacy but low side effects is of broad market prospects.F0911 is the latest development of anti-obesity drugs, previous studies have shown that the drug has weight loss effect. In order to study the drug metabolism in vivo, there are studies of the analyse method of F0911, and experiments obout the pharmacokinetic in beagle dogs were done.The thesis consists of two parts.Partâ… 0bjective:To develop a HPLC/MS method for the determination of F0911 in plasma of beagle dog and verify it.Methods:Use diazepam as the internal standard. The chromatographic separation was achieved on a Shimadzu column(150mm×2.0mm, 5μm) with mobile phase of 10mmol/L Ammoniumformate–Methanol (15:85).The flow rate was 0.22mL/min and the column temperature was 30℃. MS detection: ESI positive ion-selective detection.Results : The standard curve was lineared in the range of 7.50ng/mL～7500.00ng/mL (r=0.9998). The within day precisions in three days were between 98.30%～119.00%, and the relative standard deviations (RSD) were between 7.97%～10.38% for the low concentration and between 2.10%～4.95% for the middle and high concentration, respectively. The between days precisions were between 101.01%～106.19%, and the RSD were 7.49%, 3.55% and 4.60% for the low concentration, middle concentration and high concentration, respectively.The relative recoveries were between 103.38%～106.78%, and the RSD were 10.38%, 4.00% and 4.36% for the low concentration, middle concentration and high concentration, respectively. The extrat recoverie were between 80.50%～93063%, and the RSD were8.05%, 3.63%, and 3.33% for the low concentration, middle concentration and high concentration, respectively. The matrix extrat recoverie were between 96.80%～102.74%, and the RSD were 7.61%,4.82% and 5.44% for the low concentration, middle concentration and high concentration, respectively. Conclusions : The method is of high sensitivity, precision and reproducibility.It can determine the content of F0911 in beagle dog plasma accurately. It can be used to the pharmacokinetic studies of F0911 in beagle dog plasma.Partâ…¡Objective: About a newly synthesized anti-obesity drugs(F0911), make animal research and test the biological samples to study the drug's bioavailability and other pharmacokinetic parameters. Methods:A number of beagle dogs were the study object, which were grouped randomLy and changed the group later to do the experemrnt. Each group of the animals were administered by oral or intravenous injection,respectively, for F0911 for 10mg/kg, and blooded after the administration.The number of blood was more than 11 points for each dog. The blood were prepared to plasma. Then the investigation of the Pharmacology data of F0911 was taken by the comparison of two different administration routes, by stomach(Po.) and by intravenous injection(iv.). With the HPLC/MS method established wetested the concentration of F0911 in beagle dog plasma and studied the absolute bioavailability and the related dynamics parameter of medicine generation of F0911 in beagle dog. Results:The main pharmacokinetics parameters of F0911 in beagle dogs were as follows: the average retention time (MRT _0～t) of intravenous injection to oral administration were around the ratio of 0.7;the area under curve (AUC _0～t) were 1.89×10⁵ng/ml×min and 4.38×10⁵ng/ml×min,respactly;the clearance(CL)were 49.08mL/min/kg and 22.80mL/min/kg,respactly;the max concentration time(T_max ) were 120min and 2min,respactly;the max concentration (C_max) were 499.06ng/mL and 2611.03ng/mL,respactly.Conclusions:The absolute bioavailability of F0911 was 43.13%.The animal experiment shew that the beagle dogs oral administration of the drug was of good compliance, no obvious side effects found yet, so the drug may be considered for oral administration.