Pharmacokinetics and estimated bioavailability of grapiprant, a novel selective prostaglandin E2receptor antagonist, after oral administration in fasted and fed dogs.
OBJECTIVE
To assess the effect of food intake on the pharmacokinetics of grapiprant administered orally at 2 mg/kg, and to estimate its oral bioavailability in dogs.


METHODS
Eight healthy female Labrador Retriever dogs, aged 4-10 years were used. In the initial trial two dogs were administered a 0.5 mg/kg I/V bolus of grapiprant dissolved in ethanol. In the second trial, six dogs were assigned to two treatment groups, using a randomised cross-over design, and received 2 mg/kg of grapiprant orally, as pure powder, after fasting for 12 hours or after being fed. Blood samples were collected at preassigned times up to 36 hours after administration, and concentrations of grapiprant in plasma determined using validated high performance liquid chromatography.


RESULTS
After I/V administration in the two dogs the terminal half life was 5.30 and 6.06 hours, clearance was 444 and 476 mL/hours/kg, and volume of distribution was 3,642 and 3,883 mL/kg. Compared with fasted dogs, oral administration in fed dogs resulted in reduced median peak concentrations in plasma (1,598 vs. 614 ng/mL) and delayed median time of peak concentration (1.0 vs. 3.0 hours). The estimated bioavailability in fasted and fed dogs was 111.9 and 59.1%, respectively. Concentrations of grapiprant in plasma following oral administration, in either fed or fasted dogs, remained higher than 164 ng/mL for up to 6 hours. This concentration has been estimated to be the minimal effective concentration required to control pain in dogs.


CONCLUSIONS
Oral administration of 2 mg/kg grapiprant in fed and fasted dogs resulted in different pharmacokinetics of the drug, but did not influence the length of time when concentrations in plasma exceeded theoretical effective concentrations. Further studies are necessary to verify these findings using pharmacokinetic-pharmacodynamic studies and in clinical subjects.
a Department of Pharmacology , University of Life Sciences , Lublin , Poland.
B
B
Łebkowska-Wieruszewska
b Department of Veterinary Sciences , University of Pisa , Via Livornese (lato monte), San Piero a Grado, Pisa , Italy.
G
G
Barsotti
c Department of Cattle Breeding and Protection of Genetic Resources , University of Life Sciences , Lublin , Poland.
A
A
Lisowski
b Department of Veterinary Sciences , University of Pisa , Via Livornese (lato monte), San Piero a Grado, Pisa , Italy.
A
A
Gazzano
d School of Veterinary Science , The University of Queensland , Gatton Campus, Gatton, Queensland 4343 , Australia.
H
H
Owen
b Department of Veterinary Sciences , University of Pisa , Via Livornese (lato monte), San Piero a Grado, Pisa , Italy.
M
M
Giorgi
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004285:Dogs; D005215:Fasting; D005260:Female; D006207:Half-Life; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors*; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007093:Imidazoles; D011725:Pyridines; D000096926:Benzenesulfonamides
D058307:Receptors, Prostaglandin E, EP2 Subtype; D013453:Sulfonylurea Compounds; C522837:grapiprant; D007093:Imidazoles; D011725:Pyridines; D000096926:Benzenesulfonamides
Bioavailability; EP4 receptor antagonist; dogs; grapiprant; pharmacokinetics