A Clinical Pharmacokinetic Study Of Fluorouracil Sustained Release Implant In Patients With Malignant Pleural Or Peritoneal Effusions

Purpose To investigate the clinical pharmacokinetics of fluorouracil sustained release implant (FSRI) administered intrapleurally or intraperitoneally in the patients with malignant pleural effusions or ascites.Methods Eligible patients had moderate or large malignant pleural effusions or ascites, adequate organ function, and no anticancer therapy in the preceding 4 weeks. FSRI was administered intrapleurally or intraperitoneally at a fixed dosage of 1500 mg. The pleural or peritoneal effusions were obtained before and after administration (0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, 120, 240, 360 h). Four patients'plasma samples were also collected from the median cubital vein. Concentrations of 5-Fu were measured by high performance liquid chromatographic method (HPLC). Pharmacokinetics parameters were calculated. Distribution characteristics of fluorouracil sustained release implant in the effusions and plasma as well as the significance were analyzed. The toxicity was also observed.Results Twelve patients were enrolled. At hour 0.25 after administration, the concentrations of fluorouracil in the effusions were significantly higher than the inhibitory concentration, and at hour 4 reached peak. With the controlled-release technology, drugs released slowly, and the concentrations in the effusions were still more than the effective concentration at the 15th day. The volume of distribution (Vd) was great with small area under the curve (AUC), suggesting that drugs were mainly distributed in the pleural (peritoneal) effusions where 5-Fu concentration was significantly higher than that in plasma (t = 7.966, P < 0.05).The 5-Fu concentration in plasma was positively correlated with those in pleural or peritoneal effusions (γ5 = 0.718,γ6 = 0.837,γ8 = 0.724,γ10 = 0.622, P < 0.05). About 8 hours plasma concentrations of 5-Fu reached the peak (0.039±0.019) ug / ml, and then declined slowly over time. After the peak, plasma concentrations fluctuated slightly, and had no significant differences between different time points (F = 0.713, P = 0.622). Neither significant systemic toxicity nor local responses such as ulcers or necrosis were observed. It is considered that 5-Fu concentrations in the pleural effusions were significantly higher than that in peritoneal corresponding with that the volume of ascites is much more than the pleural effusions, and the area of peritoneum is larger which may has a faster absorption. It was suggested that the metabolism of the implants was various because of individual differences.Conclusions When administered intrapleurally or intraperitoneally fluorouracil sustained release implant has a long elimination and a slight plasma concentration fluctuation. Drugs reached the effective concentrations fast, and had high local concentrations, which was expected to enhance the effect of chemotherapy. Plasma concentrations were so slow and stable that the systemic toxicity was slight and well tolerated. Because of a prolonged exposure to 5-Fu, the number of puncture was reduced, which could reduce not only the suffering of patients but also the injury and infection. It is considered that fluorouracil sustained release implant administered intrapleurally or intraperitoneally has potential pharmacokinetic advantages.