Multi-targeted antifolate (MTA): pharmacokinetics of intraperitoneal administration in a rat model

Aims: LY 231514 or MTA is a multi-targeted antifolate which has been used a s an anticancer drug. It is an analogue of folic acid which has shown antit umour activity against various malignancies, particularly mesothelioma and colon cancer. For cancers with peritoneal surfaces extension, the advantage of intraperitoneal chemotherapy over intravenous chemotherapy administrati on is the high drug concentration that can be achieved locally. Using a rat model, this study was designed to compare the pharmacokinetics and tissue adsorption of intraperitoneal vs intravenous MTA. Methods: Sprague-Dawley rats were randomized into three groups according to dose and route of delivery of chemotherapy (10mg/kg: intravenous; 10 mg/kg : intraperitoneal; 100 mg/kg: intraperitoneal). During the course of the ex periment, peritoneal fluid and blood were sampled using a standardized prot ocol. At the end of the 3 hour procedure the rats were sacrificed, all urin e was extracted and selected tissue samples were taken. One additional rat was studied over a 6 hour period for each group. The concentration of MTA i n all samples was determined by high performance liquid chromatography (HPL C). Results: When MTA was delivered at 10 mg/kg the area under the curve (AUC) of the peritoneal fluid was significantly higher with intraperitoneal admin istration (10 778 mug/ml x min) compared to intravenous administration (454 mug/ml x min) (P<0.0001). This represents a 24-fold increase in exposure f or tissues at peritoneal surfaces after intraperitoneal administration. The AUC ratio (AUC peritoneal fluid/AUC plasma) was 40.8 for intraperitoneal d elivery as opposed to 0.014 for intravenous delivery (P=0.0063). The AUC ra tio for intraperitoneal MTA at 100 mg/kg was 19.2. The half-life of MTA in the peritoneal fluid after intraperitoneal infusion was approximately 2 hou rs. There was a significant difference in MTA concentration in the mesenter ic nodes and the abdominal wall (P=0.0036 and 0.0017) and in the kidneys (P =0.0122) when intraperitoneal and intravenous administration were compared. Other tissue samples did not demonstrate any difference in drug concentrat ion. Conclusion: These experiments demonstrated that the exposure of peritoneal surfaces to MTA is significantly increased with intraperitoneal MTA adminis tration. Due to the high likelihood of microscopic residual disease after r esection of intra-abdominal malignancies, clinical studies to evaluate intr aperitoneal MTA may be indicated. (C) 2000 Harcourt Publishers Ltd.