Pharmacokinetics studies and toxicity profile of raltitrexed used by intraperitoneal route in normothermia in a pig model

To define the pharmacokinetic and toxicity profile of raltitrexed administered by intraperitoneal route in a normothermic pig model. Twenty-one female pigs were divided in three groups. Under general anesthesia, pigs in groups 1 and 2 underwent laparotomy with resection of a small hepatic wedge, bowel anastomosis and portal and systemic vein catheterization. This was followed by an intraperitioneal delivery of raltitrexed: a dose of 1 mg was given to group 1 pigs, whereas group 2 received 2 mg. Serial sampling of portal blood, systemic blood and peritoneal fluid was then undertaken in both groups for pharmacokinetics studies. Pigs were followed daily for a period of 10 days after surgery with recordings of signs of toxicity. On day 10, an exploratory laparotomy was undertaken on each pig in order to assess peritoneal toxicity after which they were euthanized. Pigs in group 3 were used for bioavailability evaluation. Three deaths were recorded within 24 hours of surgery; a technical problem was identified in all cases and no deaths were the results of raltitrexed toxicity. A peritoneo-plasma gradient of 100:1 was obtained. Cmax in plasma were of 28 ng/ml and 54 ng/ml for group 1 and 2, respectively. Tmax were 180 min for both groups. AUCplasmatic was double in the 2 mg group compared to the 1 mg group. Raltitrexed administered by IP route in pigs is non-toxic. Pharmacologically, there are few interindividual variations and the small first-past effect did not significantly alter the high peritoneo-plasmatic gradient