| Colorectal cancer is one of the most common malignant tumor to humanhealth，predominantly surgical comprehensive treatment is the basic principles of rectalcancer treatment, the recurrence and metastasis after radical surgery is still is a key tolong-term efficacy in patients. Postoperative adjuvant chemotherapy can effectively killor inhibit the tumor cells of patients with rectal cancer,which can improve disease-freesurvival and overall survival significantly. Fluorouracil is one of classic drugs forcolorectal cancer chemotherapy, systemic chemotherapy (oral or intravenous dosing) isthe the most commonly used method. But systemic chemotherapy to local drugconcentration is low, continuous use can appear bone marrow suppression, leukopeniaand mucosal inflammation and other side effects, because of stimulus can result inphlebitis or endarteritis, limiting its use dose and cycle.Sustained-release fluorouracil for implantation of the biological histocompatibilitygood medical polymer and organic combination is a new long-acting sustained-releasefluorouracil implants. Because of its unique dosing method and the obvious regionalchemotherapy of pharmacokinetic advantage, especially suitable for intraoperative treatment. Transplanted tumor and easy recurrence, transfer parts to produce local tissueconcentration about the minimum effective concentration treatment several times to onethousand times, and reducing systemic side effects of drugs and to overcome theresistance of tumor cells. And through peripheral venous chemotherapy or oralchemotherapy is completely unable to obtain these pharmacokinetic advantage.Although there has been more pharmacokinetic studies of sustained-releasefluorouracil for implantation in recent years, but as pharmacokinetic complex, theindividual difference is big, the body metabolism is influenced by many factors.Therefore, when in clinical medicine, need to establish individualized dosage regimen,and the population pharmacokinetic is an effective way to design individualizedtreatment plan. There are no population pharmacokinetic research reports aboutsustained-release fluorouracil for implantation in colorectal cancer patientsThis experiment by means of fluorouracil implants compared with the traditionalpreparation of pharmacokinetic study, verify the implanted with pharmacokineticadvantage of fluorouracil sustained release preparations. Using the clinicalpharmacokinetics of sustained-release fluorouracil for implantation of scattered data,establishing fluorouracil implants in patients with rectal cancer populationpharmacokinetic model, quantitatively reflect the average level of whole group andindividual relation of quantitative biology, estimate the population pharmacokineticparameters, which the drug is safe and effective application to provide theoretical basisfor clinical treatment of colorectal cancer. The main contents are given as follows:1. Establish the method of Fluorouracil implants blood drug concentration analysisExperiment by measuring blood drug concentration of fluorouracil implants, to reflect the changes of blood drug concentration in colorectal cancer. This article usedthe liquid-liquid extraction method and treatment of biological sample, has establishedHPLC analysis methods of fluorouracil implants in patients with colorectal cancer.Chromatographic conditions are: chromatographic column: Hypersil C18produced byDalian elite(250mm×4.6mm,5μm)；moving phase: Methanol: water(5∶95)；flowvelocity:1.0mL/min； Wavelength ultraviolet spectrophotometry:263nm； columntemperature:25℃; This paper established the biological sample pretreatment methodand reverse phase high performance liquid chromatography separation anddetermination of fluorouracil in biological samples of content, high recovery rate,chromatographic separation, high selectivity. This quantitative range and linearspecificity requirements for precision and accuracy are achieved in vivo drug analysis.The method was successfully applied to fluorouracil implants of blood drugconcentration in patients with rectal cancer.2．Pharmacokinetic study of fluorouracil implants40patients with colorectal cancer according to the different method of drugdelivery were randomly divided into2groups: sustained-release fluorouracil implants in20cases,20cases5-fluorouracil systemic chemotherapy group. High performanceliquid chromatography (HPLC) determination of blood drug concentration, comparedtwo groups of patients with5-fluorouracil half-life, medicine when the curve (AUC) inthe area and the apparent volume of distribution (Vd).5-fluorouracil implantsslow-release half-life is119.044±22.171h, in the body to maintain effectiveconcentration (>0.1ug/ml) of up to240hours, and two groups of patients with rectalcancer in t, AUC and there is statistical difference between Vd. By comparing the two5-fluorouracil drug delivery approaches in pharmacokinetic studies in patients with rectal cancer, concluded that5-fluorouracil implants pharmacokinetic advantage ofslow-release chemotherapy.3Population pharmacokinetic study of fluorouracil implantsRetrospective sampling method extracting fluorouracil implants group bloodconcentrations of120patients with rectal cancer. Blood drug concentration measuredon the basis of one room model, using NONMEM to set up the model of Populationpharmacokinetic. Get average blood drug concentration time curve.then calculate thepopulation pharmacokinetic parameters: Kr:0.00544±0.00289h-1, Ka:0.748±0.602h-1V/F:1.06±0.343L·Kg-1, CL/F:262±0.194L·Kg-1,1000participants blood drugconcentration according to data from the simulation basic covers the90%confidenceinterval of the measured values, confirmed the reliability of the simulation results. Thispaper successfully established5-fluorouracil implants of population pharmacokineticmodel, it can estimate the individual pharmacokinetic parameters to predict blood drugconcentration, to give the theoretical guidance for individual patients with rectal cancertreatment. |
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