Pharmacokinetics and tissue distribution of intraperitoneal 5-fluorouracil with a novel carrier solution in rats

To compare the pharmacokinetics and tissue distribution of 5-fluorouracil administered intraperitoneally with two isotonic carrier solutions: HAES-steri (neotype 6% hydroxyethyl starch), a novel carrier solution with middle molecular weight and physiologic saline (0.9% sodium chloride solution), a traditional carrier solution for intraperitoneal chemotherapy, in rats.

A total of 60 Sprague Dawley rats were randomized into groups according to the carrier solution administered. Each group was further randomized according to the intraperitoneal dwell period (1, 3, 6, 12, 18 and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and quantitated. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography.

The mean volumes remaining in the peritoneal cavity were significantly higher with HAES-steri than those with physiologic saline at 1, 6, 12, 18, and 24 h (P = 0.047, 0.009, 0.005, 0.005 and 0.005 respectively, the percentages of remaining peritoneal fluid volume were 89.9 +/- 5.6 vs 83.4 +/- 4.9, 79.9 +/- 2.8 vs 56.2 +/- 15.7, 46.8 +/- 5.5 vs 24.7 +/- 9.7, 23.0 +/- 2.8 vs 0.0 +/- 0.0 and 4.2 +/- 1.7 vs 0.0 +/- 0.0 respectively). Mean concentrations in peritoneal fluid were significantly higher with HAES-steri than those with physiologic saline at 3, 12 and 18 h (P = 0.009, 0.009 and 0.005 respectively, the concentrations were 139.2768 +/- 28.2317 mg/L vs mg/L, 11.5427 +/- 3.0976 mg/L vs 0.0000 +/- 0.0000 mg/L and 4.7724 +/- 1.0936 mg/L vs 0.0000 +/- 0.0000 mg/L respectively). Mean plasma 5-fluorouracil concentrations in portal vein were significantly higher with HAES-steri at 3, 12, 18 and 24 h (P = 0.009, 0.034, 0.005 and 0.019 respectively, the concentrations were 3.3572 +/- 0.8128 mg/L vs 0.8794 +/- 0.2394 mg/L, 0.6203 +/- 0.9935 mg/L vs 0.0112 +/- 0.0250 mg/L, 0.3725 +/- 0.3871 mg/L vs 0.0000 +/- 0.0000 mg/L, and 0.2469 +/- 0.1457 mg/L vs 0.0000 +/- 0.0000 mg/L respectively), but significantly lower at 1 h (P = 0.009, the concentrations were 4.1957 +/- 0.6952 mg/L vs 7.7406 +/- 1.2377 mg/L). There were no significant differences in the plasma 5-fluorouracil in inferior caval vein at each time-point. 5-fluorouracil concentrations were significantly greater with HAES-steri at 18 h in gastric tissue (P = 0.016, the concentrations were 0.9486 +/- 0.8173 mg/L vs 030392 +/- 0.0316 mg/L), at 18 h in colon (P = 0.009, the concentrations were 0.1730 +/- 0.0446 mg/L vs 0.0626 +/- 0.0425 mg/L), at 3, 6, 12 and 24 h in liver (P = 0.009, 0.013, 0.034 and 0.013 respectively, the concentrations were 0.6472685 +/- 0.5256 mg/L vs 0.1554 +/- 0.1043mg/L, 0.8606826 +/- 0.7155 mg/L vs 0.0014 +/- 0.0029 mg/L, 0.0445 +/- 0.0330 mg/L vs 0.0797 +/- 0.1005 mg/L and 0.0863 +/- 0.0399 mg/L vs 0.0034 +/- 0.0075 mg/L respectively) and at 18 h in lung (P = 0.009, the concentrations were 0.0886 +/- 0.0668 mg/L vs 0.0094 +/- 0.0210 mg/L). There were no differences in 5-fluorouracil concentrations in renal tissue at each time-point.

The use of intraperitoneal 5-fluoro-uracil with HAES-Steri carrier solution provides a pharmacokinetic advantage for a local-regional killing of residual tumor cells and improve the accumulated penetrability of 5-fluorouracil with decreased systemic toxicity. Further clinical feasibility studies on the use of HAES-steri as carrier solution for intraperitoneal chemotherapy with 5-fluorouracil are warranted.