Pharmacokinetics And Tissue Distribution Of Intraperitoneal Aerosol 5-Fu In Rats

Background and Objectives With the continuous improvement of living standards, gastrointestinal cancer has become a serious threat to human health, one of the major diseases, morbidity and mortality are high, and has been dropping.At present the treatment of gastrointestinal cancer surgery is still dominated by the comprehensive treatment of the first cases of doctors from Billroth gastrectomy has been more than 120 years, gastrointestinal tumor surgery to remove the tumor from only concerned with removal of the primary tumor and the invaded organ, the elimination of regional lymph nodes and kill off cancer cells in the surgical treatment of abdominal cavity; from a single surgical access to standardized perioperative therapy plus surgery to new treatment modalities. However, since medical treatment was found in patients with gastrointestinal cancer is already in progress when the most advanced, after a radical mastectomy is still about half of the patients had local recurrence within 5 years and/or distant metastasis.Intraperitoneal free cancer cells (free cancer cell, FCC), and can not be completely resected the existence of small foci caused by intraperitoneal gastrointestinal tumor recurrence and/or distant metastasis of the main factors, affects the long-term survival the direct cause. Scholars have made unremitting efforts to this end, including preoperative arterial infusion chemotherapy, the intestine surgery chemotherapy, preoperative chemotherapy combined with perioperative adjuvant chemotherapy, etc..In recent years, intraperitoneal chemotherapy (intraperitoneal chemotherapy, IPC) in particular, intraperitoneal hyperthermic chemotherapy (continuous hyperthermic peritoneal perfusion chemotherapy, CHPPC) because of its unique pharmacokinetic characteristics, and other basic characteristics of much attention. The results show that abdominal chemotherapy could be effective prevention and treatment of gastrointestinal cancer after surgery area, peritoneal and hepatic recurrence, and the large sample case study found that recurrence of gastrointestinal cancer the most common anatomic site surgery, regional,abdominal aortic lymph nodes, peritoneal surfaces, ovaries and other pelvic floor and, after the most common sites of metastasis is the liver. Because "peritoneal-plasma screens,"the existence of the concentration of intraperitoneal chemotherapy drugs can be several times the concentration of intravascular administration or even several times, in the abdominal cavity to provide a constant sustained high concentrations, greatly strengthened the role of anticancer drugs,the relevant literature reported that intraperitoneal chemotherapy in particular, intraperitoneal hyperthermic perfusion chemotherapy on 3-5mm of tumor nodules is effective.Laparoscope in gastrointestinal cancer therapy is carried out in recent years, a new technology, such as self-Jacob reported the first application of laparoscopic colorectal surgery has been reported in this field at home and abroad increased, the formation of the gastrointestinal Road surgery in a trend.Need to establish pneumoperitoneum in laparoscopic surgery in order to reveal the operative field, the eddy current effect of pneumoperitoneum can be open abdominal spread of cancer cells to fall off, resulting in puncture and peritoneal metastasis, and early in 1978, Dobronnate so the first time Cancer CO2 pneumoperitoneum laparoscopic surgery can cause the spread of cancer cells and metastasis. Therefore, how to take reasonable measures to prevent the laparoscopic treatment of gastrointestinal cancer recurrence after surgery within the abdominal cavity and/or distant metastasis for improving the prognosis and survival of great importance.The subject of the use of chemotherapy instrument developed by the aerosol mist of the 5-Fu after the implementation of animal peritoneal perfusion to study the aerosol in vivo state of 5-Fu in the blood and tissue distribution of the drug on behalf of the establishment mathematical model of the development and applications for the clinical laboratory and theoretical basis. Purpose1.Developed 5-Fu can be atomized liquid into gas in animals aerosol chemotherapy device, without changing the chemical nature of chemotherapy drugs.2.Chromatographic analysis of conditions and the establishment of 5-Fu in the peritoneal fluid, portal vein, inferior vena venous blood, stomach, colon, liver, kidney, lung tissue standard curve.3.High performance liquid chromatography (HPLC) determination of peritoneal fluid, portal vein, inferior vena venous blood, stomach, colon, liver, kidney, lung tissue concentrations of 5-Fu.4.Pharmacokinetic parameters were calculated, and plotted the average concentration of drug when the fitting curve.Methods1.Need to establish pneumoperitoneum in laparoscopic surgery in order to reveal the operative field, CO2 gas on the body chemical, immunological and molecular biology of peritoneal free cancer cells makes it easier to grow in the abdominal cavity off. Therefore, we envisage the possibility of chemotherapy drugs by spray into the abdominal cavity in order to achieve free to kill cancer cells, is consistent with traditional principles of intraperitoneal chemotherapy, but also more extensive contacts peritoneum, and side edge surgery chemotherapy, simplifying the treatment process.According to this idea we designed and developed that can be connected with pneumoperitoneum simple ultrasound instrument aerosol chemotherapy.2.Nanfang Hospital, Southern Medical University Experimental Animal Center of the clean laboratory Sprague-Dawley (SD) rats weighing 200-300g, a total of 30 rats were randomly divided into 1h,3h,6h,12h,18h,24h time point group, each time point were randomly divided to five.3.By ether inhalation anesthesia, the rats were fixed on the operative table, and built a cotton ball in 50ml syringe additional ether anesthesia (needle fixed on the rat nostril).Rats were placed in abdominal needle left, right lower quadrant, left lower quadrant puncture aerosol chemotherapy connected device,, using STROZ aerosol machine to maintain pressure of pneumoperitoneum about 8mmHg, gas flow rate of about 5L/min, catheters placed in the right lower abdomen, below the water surface. When 5-Fu (0.1ml/g) aerosol after reperfusion in each group at 1h,3h,6h,12h,18h, 24h with abdominal midline incision laparotomy, peritoneal fluid, portal vein and blood samples from the inferior vena 2ml,followed by Remove the liver, stomach, colon, kidney, lung 5-Fu concentration measurement equipment.4.Chromatographic analysis of conditions and the establishment of 5-Fu in the peritoneal fluid, portal vein, inferior vena venous blood, stomach, colon, liver, kidney, lung tissue standard curve.5.The samples were obtained after pretreatment with high performance liquid chromatography in which the concentration of 5-Fu.6.Pharmacokinetic parameters were calculated, and plotted the average drug concentration curve time.7.5-Fu concentration-time data with the Drug and Statistics (DAS) 2.0 software, intelligent calculation to determine the appropriate model,weight selection, based upon automatically computing the best fit parameters given conditions, in different tissues and body fluids 5-Fu distributed the best AV, non-compartment model and the corresponding pharmacokinetic parameters;using DAS 2.0 software to map out the organization and the body fluid 5-Fu and the average concentration-time curve to be, if the data is too small, The software can not be and when, is mapped using OriginPro 7.5 5-Fu concentration trends over time.Result1.Peritoneal fluid, portal vein and inferior vena cava blood, colon, stomach, liver, kidney and lung tissue concentration peak in 1h group, all drug concentrations over time showed a decreasing trend; peritoneal fluid drug concentration in the 1h group in the peak (259.7730ug/ml);portal vein (PV), blood level higher concentration in the 1h group (7.4933ug/ml) is the inferior vena cava (ICV) blood (5.5930ug/ml) of about 1.3 times;the highest concentration of renal tissue,1h group concentration (2.4030ug/ml),lung, stomach concentration of the second, colon, liver tissue concentration of the lowest order.2.Biological samples in the impurity exclusion chromatographic conditions, was 5-Fu plasma standard curve for the c=26.2180A/Ais-0.09966, r=0.9998,linear range:0.001μg/ml-10μg/ml.5-Fu peritoneal fluid obtained standard curve①c =28.4286A/Ais-2.2667, r=0.9988,linear range:0.001μg/ml-50μg/ml;②c= 65.491 lA/Ais-58.7932, r=0.9989 linear range:50μg/ml-2000μg/ml.5-Fu gastric tissue was standard curve for the c=29.0487A/Ais-3.2353,r=0.9991,linear range:0.001μg/ml-50μg/ml.5-Fu colon was standard curve for the c 24.9276A/Ais-1.2175,r=0.9997, linear range:0.001μg/ml-50μg/ml.Was 5-Fu liver standard curve for the c=25.4524A/Ais-0.0135, r=0.9999, linear range:0.001μg/ml-50μg/ml. Was 5-Fu kidney standard curve for the c 25.7613A/Ais-0.3486, r=0.9994,linear range:0.001μg/ml-50μg/ml.5-Fu in lung tissue obtained standard curve for the c=28.1921A/Ais-0.2214, r=0.9998, linear range:0.001μg/ml-50μg/ml.3. Come to different tissue and body fluid distribution of 5-Fu in the best AV, non-compartment model and the corresponding pharmacokinetic parameters, and drawing the average drug concentration time curve fitting.Conclusion1.The issue from the perspective laparoscopic cholecystectomy intraperitoneal chemotherapy, the animals underwent chemotherapy drug aerosolization intraperitoneal perfusion study the pharmacokinetics and to establish the pharmacokinetic model, so that abdominal chemotherapy could become aerosol Laparoscopic surgery perioperative intraperitoneal chemotherapy for the treatment of the new model, the treatment of gastrointestinal cancer and the whole abdominal cavity abdominal cancer recurrence and/or distant metastasis has a certain application.2.This study established the determination of SD plasma, peritoneal fluid and the major tissues of 5-Fu content of high performance liquid chromatography, serum and tissue of impurities do not interfere with the determination of 5-Fu; extraction recovery of high-sensitive high specificity, pretreatment simple time-saving,5-Fu is suitable for studying the pharmacokinetics.