Impact of carrier solutions on pharmacokinetics of intraperitoneal chemotherapy

Purpose: In the treatment of gastrointestinal malignancies with disseminati on to peritoneal surfaces the principal advantage of intraperitoneal chemot herapy over intravenous chemotherapy is the high drug concentration achieve d locally with low systemic toxicity. This advantage can be optimized by ma intaining a large area of contact between the chemotherapy solution and the surfaces within the abdomen and pelvis over a prolonged time period. Using a rat model we compared the pharmacokinetics of two drugs infused intraper itoneally, 5-fluorouracil and gemcitabine, in five different carrier soluti ons. Methods: A total of 120 Sprague Dawley rats were randomized into group s according to the carrier solution and the drug administered. Rats were gi ven a single dose of intraperitoneal 5-fluorouracil (20 mg/kg) or gemcitabi ne (12.5 mg/kg) in 0.1 ml/g body weight of each carrier solution. The carri er solutions used varied in their tonicity (0.3%, 0.9% or 3% sodium chlorid e), or were isotonic and varied in molecular weight (0.9% sodium chloride, 4% icodextrin and 6% hetastarch). With the hypotonic, isotonic and hyperton ic sodium chloride solutions, only 5-fluorouracil was used. Each group was further randomized according to the intraperitoneal dwell period (1, 3 or 6 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the blood was sampled using a standardized pr otocol. The volume of the peritoneal fluid was recorded, and the drug conce ntrations in the peritoneal fluid and plasma were determined by high-perfor mance liquid chromatography. Results: Measurements of peritoneal fluid volu me showed a more rapid clearance of hypotonic and isotonic sodium chloride solutions from the peritoneal cavity as compared to hypertonic sodium chlor ide and high molecular weight solutions. When comparing the remaining intra peritoneal volumes at 6 h, the differences were statistically significant f or both 5-fluorouracil and gemcitabine when hetastarch (P<0.0001 and P=0.00 04) and icodextrin (P=0.002 and 0.008) were compared with isotonic sodium c hloride solution. Similarly, there was a significant difference in the volu mes recorded at 6 h when hypotonic (P<0.0001) and isotonic sodium chloride solutions (P=0.0002) were compared with hypertonic sodium chloride solution . The concentrations of chemotherapy in the different carrier solutions var ied little. The total amount of drug in the peritoneal cavity decreased wit h all solutions and more quickly with 5-fluorouracil than with gemcitabine. There was a significant difference in the total intraperitoneal 5-fluorour acil between hypotonic and isotonic sodium chloride solutions at 1 h (P = 0 .0003) and 3 h (P = 0.0043), as well as between the isotonic and hypertonic sodium chloride solutions at 1 h (P = 0.03) and 3 h (P < 0.0001). Similarl y, there was a significant difference in the total peritoneal gemcitabine a t 6 h between icodextrin and isotonic sodium chloride solution (P=0.01) and between hetastarch and isotonic sodium chloride solution (P = 0.05). There were no significant differences in plasma 5-fluorouracil and plasma gemcit abine concentrations obtained with the five solutions. Conclusions: These f indings show that the clearance of 5-fluorouracil and gemcitabine from the peritoneal cavity can be significantly modified by varying the tonicity or the molecular weight of the carrier solution. Peritoneal fluid clearance wa s slower with hypertonic sodium chloride and high molecular weight solution s and this resulted in a reduced clearance of chemotherapy. By using a high molecular weight carrier solution the exposure of intraperi toneal cancer cells to gemcitabine was prolonged and drug availability at t he peritoneal surface was increased. Similarly, by using a hypertonic carri er solution the exposure to 5-fluorouracil was prolonged and drug availabil ity at the peritoneal surface was also increased.