title: Pharmacokinetics and the effect of heat on intraperitoneal pemetrexed using a murine model.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Maisonneuve-Rosemont Research Center, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, QC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Badrudin
authors.affiliation: Maisonneuve-Rosemont Research Center, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, QC, Canada.
authors.forename: Camille
authors.initials: C
authors.lastname: Perrault-Mercier
authors.affiliation: Maisonneuve-Rosemont Research Center, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, QC, Canada.
authors.forename: Antoine
authors.initials: A
authors.lastname: Bouchard-Fortier
authors.affiliation: Maisonneuve-Rosemont Research Center, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, QC, Canada.
authors.forename: Julien
authors.initials: J
authors.lastname: Hubert
authors.affiliation: Maisonneuve-Rosemont Research Center, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, QC, Canada.
authors.forename: François A
authors.initials: FA
authors.lastname: Leblond
authors.affiliation: Maisonneuve-Rosemont Research Center, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, QC, Canada.
authors.forename: Lucas
authors.initials: L
authors.lastname: Sideris
authors.affiliation: Maisonneuve-Rosemont Research Center, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, QC, Canada. Electronic address: pierredube@videotron.qc.ca.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubé
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006358:Hot Temperature; D007274:Injections, Intraperitoneal; D008297:Male; D023421:Models, Animal; D000068437:Pemetrexed / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010537:Peritoneum / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D000068437:Pemetrexed
keywords: Cytoreductive surgery; HIPEC; Pemetrexed; Peritoneal mesothelioma; Pharmacokinetics