大容积加温低渗5-FU腹腔化疗预防胃癌术后复发和肝转移的药代动力学研究

背景与目的:目前,有关腹腔化疗药代动力学研究仅见于个别动物实验报告;本研究是探讨胃癌根治术后即时大容积、加温、低渗5-氟尿嘧啶(5-FU)液腹腔化疗药代动力学变化。方法:选择行胃癌根治术病人50例,关腹后即时经腹腔引流管快速注入43℃-45℃蒸馏水5-FU(500mg/L)液1250ml/m2。将上述50例病人按样本收集时间不同随机分为10组(每组5例),分别于注药后即刻、注药后5min、15min、30min、45min和1、3、6、12、24h抽取股动脉、股静脉、门静脉血样和腹腔液。同时选择准备行胃癌根治术病人25例,随机分为5组(每组5例),分别于术前1、3、6、12、24h经右下腹穿刺快速注入同样药液,开腹后立即抽取门静脉血样。以高效液相色谱法测定上述样本中5-FU浓度。结果:腹腔液峰浓度在腹腔给药结束后0h,门静脉血峰浓度在腹腔给药结束后15min,股动、静脉血峰浓度均在腹腔给药结束后1h。腹腔液峰浓度和平均浓度分别是股静脉血的167.7倍和180.4倍,门静脉血峰浓度和平均浓度分别是股静脉血的5.4倍和6.7倍。5-FU在腹腔液、门静脉血、股动脉血和股静脉血中的浓度变化均符合二室开放模型,主要药代动力学参数分别为:AUC0→tn(mg·L-1·h-1)依次为3667.36,143.82,31.02,26.84;α(h-1)依次为1.1076,0.6269,7.7923,21.5643;β(h-1)依次为0.03

Pharmacokinetic study of postoperative peritoneal infusion with large bulk heated hypotonic 5-fluorouracil fluid for prevention of recurrence and hepatic metastasis of gastric cancer

BACKGROUND & OBJECTIVE: At present, only few animal experiment has been reported about the pharmacokinetic of peritoneal chemotherapy. The aim of this study was to determine the pharmacokinetic change following large bulk heated hypotonic 5-fluorouracil fluid perfusing into peritoneal immediately after radical resection. METHODS: (1) Fifty patients with gastric cancer after radical resection were randomly assigned into ten groups. They were given intraperitoneal infusion of warm (43 degrees C-45 degrees C) distilled water (1,250 ml/m2) plus 5-fluorouracil (500 mg/L) after radical gastrectomy. At various time intervals (0, 0.08, 0.25, 0.5, 0.75, 1, 3, 6, 12, 24 h), blood samples from the femoral artery and vein, portal vein, and peritoneal fluid were collected. (2) 25 cases of patients with gastric cancer were randomized into five groups, each group also included 5 cases. They were also given intraperitoneal infusion at 1, 3, 6, 12, 24 h with the same fluid before operation, blood samples from portal vein were drawn at the beginning of operation. (3) 5-fluorouracil concentration of above all of samples were determined by high performance liquid chromatography (HPLC). RESULTS: (1) The peak concentration of peritoneal fluid, portal vein, femoral artery and vein were at 0, 0.08, 1.00, 1.00 h, respectively, after peritoneal infusion. (2) The peak and average concentration in peritoneal fluid were 167.7-fold and 180.4-fold as high as that of the femoral vein respectively. (3) The peak and average concentration in portal vein were 5.4-fold and 6.7-fold as high as that of the femoral vein respectively. (4) The concentration changes of 5-fruorouracil in peritoneal fluid, portal vein, femoral artery and vein were all suitable for two compartment open model. The pharmacokinetics parameters of above all the fluid were in turn: AUC0-->tn(mg.L-1.h) 3667.36, 143.82, 31.02, 26.84; alpha(h-1) 1.1076, 0.6269, 7.7923, 21.5643; beta(h-1) 0.0367, 0.0474, 0.2091, 0.2014; CL(L.h-1) 0.16, 4.92, 35.36, 39.32; T1/2 alpha(h) 0.62, 1.11, 0.09, 0.03; T1/2 beta(h) 18.88, 14.64, 3.31, 3.44; (5) The portal vein 5-fluorouracil concentration at various times were all lower than that of the preoperation, suggesting that 5-fluorouracil can pass through retroperitoneal spaces into systemic circulation. CONCLUSION: Postoperative large bulk heated hypotonic fluid peritoneal infusion with 5-fluorouracil has pharmacokinetic characteristic of high selective regional chemotherapy providing higher and lasting concentration in peritoneal fluid and portal vein. Therefore, this method should be a more reasonable chemotherapy for the prevention of recurrence and liver metastasis of gastric cancer after radical resection.