Pharmacokinetics and the effect of heat on intraperitoneal pemetrexed using a murine model

Pemetrexed is a systemic chemotherapeutic agent used in the treatment of malignant mesothelioma. This drug represents a potentially promising intraperitoneal (IP) agent to use for hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal mesothelioma. However, this has yet to be supported by preclinical studies. Therefore, we aimed to study the effect of pemetrexed dose and perfusion temperature on the resultant pemetrexed concentration in 3 different compartments (systemic circulation, portal circulation and peritoneal tissues) using a murine model.

Under general anesthesia, 29 Sprague-Dawley rats were submitted to 3 different doses of IP pemetrexed (500, 1000 and 1500 mg/m²) combined with 3 different perfusion temperatures (37, 40 and 43 °C) for a total duration of 25 min. At the end of perfusion, samples in different compartments (systemic circulation, portal circulation and peritoneum) were harvested and concentrations of pemetrexed were measured using high performance liquid chromatography.

With increasing dose of IP pemetrexed, higher concentrations were measured in the 3 compartments tested. In peritoneal cells, the difference between IP doses of 500 and 1000 mg/m² (2.03 vs. 19.17 μg/g, p < 0.001) was greater than the difference between 1000 and 1500 mg/m² (19.17 vs. 22.80 μg/g, p = 0.027). When the perfusion temperature increased, we observed a proportional rise of pemetrexed concentration in both the portal and systemic compartments; while in the peritoneal cells, the pemetrexed concentration increased up to 40 °C, after which it plateaued.

Both heat and increasing doses of IP pemetrexed enhance peritoneal cell concentration of pemetrexed. However, for temperatures above 40 °C, pemetrexed concentration reached a plateau in peritoneal cells. Systemic and portal concentrations increased proportionally with both increasing temperatures and IP doses. We believe these results should be taken into consideration for the design of an eventual clinical study in humans.