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Pharmacokinetics and tissue distribution of intraperitoneal docetaxel with different carrier solutions
Faheez Mohamed1, O Anthony Stuart, Paul H Sugarbaker
1The Washington Cancer Institute, Washington Hospital Center, 110 Irving Street, NW, Washington, DC 20010, USA.
Background:
Intraperitoneal chemotherapy administration results in high drug concentration locally with low systemic toxicity. Using a rat model we compared the pharmacokinetics and tissue absorption of docetaxel infused intraperitoneally in two isotonic carrier solutions; 1.5% dextrose peritoneal dialysis solution (peritoneal dialysis solution) and hetastarch (6% hydroxyethyl starch), a high molecular weight solution.
Materials And Methods:
Sixty Sprague-Dawley rats were randomized into groups according to the carrier solution administered. Rats were given a single dose of intraperitoneal docetaxel (80 mg/m(2)) in 0.1 ml/g body weight of each carrier solution. Each group was further randomized according to the intraperitoneal dwell period (3, 6, 12, 18, and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the volume recorded. Blood and tissues were sampled using a standardized protocol. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography.
Results:
Hetastarch clearance from the peritoneal cavity was reduced when compared to peritoneal dialysis solution. The mean volumes remaining in the peritoneal cavity were significantly higher with hetastarch at 6 h (P = 0.022) and 12 h (P = 0.0012). Plasma docetaxel concentrations were similar for both carrier solutions. The mean total amount of docetaxel remaining in the peritoneal cavity was significantly greater with hetastarch at 3 h (P = 0.0022), 6 h (P = 0.0043), and 12 h (P = 0.0023). There was a 39% increase in the area under the curve ratio of peritoneal fluid to plasma docetaxel concentrations with hetastarch (227) versus peritoneal dialysis solution (163). Docetaxel concentrations were significantly greater with hetastarch in colonic tissue at 18 and 24 h, and in gastric tissue at 6, 12, and 18 h.
Conclusion:
The use of intraperitoneal docetaxel with a hetastarch carrier solution provides a pharmacologic advantage for a local-regional killing of residual intraperitoneal tumor cells without increasing systemic toxicity.