Pharmacokinetics of intraperitoneal gemcitabine in a rat model

Background: Gemcitabine (2'-2' difluorodeoxycytidine) has been shown to pos sess a broad spectrum of antitumor activity against various malignancies, p articularly pancreatic carcinoma. For cancers occurring within the abdomina l cavity, the advantage of intraperitoneal (ip) chemotherapy over intraveno us (iv) chemotherapy is the high drug concentration that can be achieved lo cally. In addition, the cytotoxic effect of several anticancer agents can b e enhanced by hyperthermia. Using a rat model, this study was designed to c ompare ip vs iv gemcitabine and to evaluate the effect of hyperthermia on i p gemcitabine. Methods: In the first phase of this study, 18 Sprague Dawley rats were give n 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 Daw ley 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 te mperature of the peritoneal perfusate (normothermic or hyperthermic). Durin g the course of both experiments, peritoneal fluid and blood were sampled u sing a standardized protocol. At the end of the procedure the rats were sac rificed and all urine was extracted. Selected tissue samples were taken fro m rats in the second phase of the study. The concentration of gemcitabine i n all samples was determined by high performance liquid chromatography (HPL C). Results: When gemcitabine was delivered at 12.5 mg/kg (phase 1) the area un der the curve (AUC) was significantly higher with ip administration as comp ared 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 concent rations between samples from the normothermic and hyperthermic groups, all tissue samples (except stomach) in the hyperthermic group exhibited increas ed gemcitabine concentrations. Conclusion: These experiments demonstrated that the exposure of peritoneal surfaces to gemcitabine is significantly increased with ip gemcitabine. Int raabdominal hyperthermia had no significant effect on the pharmacokinetics of ip gemcitabine but there was evidence of increased absorption of gemcita bine in most intraabdominal tissues. Due to the likelihood of a high incide nce of microscopic residual disease after resection of a pancreatic carcino ma, clinical studies to evaluate ip hyperthermic gemcitabine may be indicat ed.