A study of the effect of temperature on the pharmacokinetic profile of raltitrexed administered by intraperitoneal route in the rat.

Because heat can improve the activity of selected drugs when administered heated in the peritoneal cavity in the treatment of peritoneal carcinomatosis from colorectal origin, there is a great interest to evaluate new cytotoxic agents in this context. The purpose of this study is to assess the effect of heat on the pharmacokinetic profile of Raltitrexed administered intraperitoneally in rats.Rats #1 to #40 have been submitted to different doses of intraperitoneal Raltitrexed (2, 4, and 8 mg/m2) at different perfusion temperatures (37, 40 and 43 degrees C). After 25 minutes of perfusion, peritoneal fluid, portal and systemic blood were harvested and prepared for dosage of Raltitrexed. Rats #41 to #50 have been submitted to 8 mg/m2 of intraperitoneal Raltitrexed (37 and 43 degrees C) during 25 minutes. Then, a segment of small bowel and a section of parietal peritoneum were harvested and prepared for intracellular dosage of Raltitrexed.The dose of Raltitrexed administered is a determinant of its concentration in peritoneal perfusate, in portal vein blood and in systemic blood (p < 0.0002). We noticed that perfusate temperature had no significant effect on the concentration of drug in the portal vein blood (p = 0.29) and in the systemic blood (p = 0.25). However, temperature increased significantly (p < 0.04) the intracellular absorption of Raltitrexed.Because the effect of Raltitrexed is proportional to its intracellular concentration, it seems clear that Raltitrexed is of greatest interest when administered heated in the peritoneum because it can reach greater intracellular concentrations without a significant increase in systemic concentration, which is responsible of toxicity.