Pharmacokinetics of intraperitoneal gemcitabine in a rat model

Background: Gemcitabine (2'-2' difluorodeoxycytidine) has been shown to possess a broad spectrum of antitumor activity against various malignancies, particularly pancreatic carcinoma. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal (ip) chemotherapy over intravenous (iv) chemotherapy is the high drug concentration that can be achieved locally. In addition, the cytotoxic effect of several anticancer agents can be enhanced by hyperthermia. Using a rat model, this study was designed to compare ip vs iv gemcitabine and to evaluate the effect of hyperthermia on ip gemcitabine. Methods: In the first phase of this study, 18 Sprague Dawley rats were given a single dose of gemcitabine then randomized into three groups according to dose and route of delivery of chemotherapy (12.5 mg/kg - iv, 12.5 mg/kg - ip or 125 mg/kg - ip). In a separate experiment (phase 2), 12 Sprague Dawley rats were given a continuous ip perfusion of gemcitabine (12.5 mg/kg in 150 mt total perfusate) and randomized into two groups according to the temperature of the peritoneal perfusate (normothermic or hyperthermic). During the course of both experiments, peritoneal fluid and blood were sampled using a standardized protocol. At the end of the procedure the rats were sacrificed and all urine was extracted. Selected tissue samples were taken from rats in the second phase of the study. The concentration of gemcitabine in all samples was determined by high performance liquid chromatography (HPLC). Results: When gemcitabine was delivered at 12.5 mg/kg (phase 1) the area under the curve (AUC) was significantly higher with ip administration as compared to iv administration (P = 0.001). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 12.5 +/- 3.2 for ip delivery as opposed to 0.2 +/- 0.2 for iv delivery (P = 0.0002). The AUC ratio for ip gemcitabine at 125 mg/kg was 26.8 +/- 5.8. Although there was no significant difference in drug concentrations between samples from the normothermic and hyperthermic groups, all tissue samples (except stomach) in the hyperthermic group exhibited increased gemcitabine concentrations. Conclusion: These experiments demonstrated that the exposure of peritoneal surfaces to gemcitabine is significantly increased with ip gemcitabine. Intraabdominal hyperthermia had no significant effect on the pharmacokinetics of ip gemcitabine but there was evidence of increased absorption of gemcitabine in most intraabdominal tissues. Due to the likelihood of a high incidence of microscopic residual disease after resection of a pancreatic carcinoma, clinical studies to evaluate ip hyperthermic gemcitabine may be indicated.