Pharmacokinetic Profile of A New Diclofenac Prodrug without Gastroulcerogenic Effect
Michel Leandro de Campos,
Helen Mariana Baldan-Cimatti,
Marcelo Gomes Davanco,
Marco Antonio Ferraz Nogueira,
Elias Carvalho Padilha,
Caroline Damico Candido,
Jean Leandro dos Santos,
Rosangela Goncalves Peccinini.
Gastrotoxicity is a major problem for long-term therapy with non-steroidal anti-inflammatory drugs (NSAIDs).
DICCIC (1-(2,6-dichlorophenyl)indolin-2-one) is a new diclofenac prodrug, which has proven anti-inflammatory activity
without gastroulcerogenic effect. The aim of this work was to compare the pharmacokinetic profiles of diclofenac from
DICCIC (7.6 mg/kg equivalent to 8.1 mg/kg diclofenac) and diclofenac (8.1 mg/kg) administration in Wistar rats
weighing 250-300 g (n=20). The doses were calculated by interspecific allometric scaling based on the 2 mg/kg from
diary human dose of diclofenac. Blood samples were collected in heparinized tubes via the femoral artery through the
implanted catheter. The plasma was separated and quantitation was made in a HPLC system with a UV-Vis detector. The
confidence limits of the bioanalytical method were appropriate for its application in a preclinical pharmacokinetic study.
The AUC of diclofenac from DICCIC (53.7± 5.8 ug/mL.min) was significantly less (Mann Whitney test, p<0.05) than
that of diclofenac from diclofenac administration (885.9 ± 124,8 ug/mL.min). Terminal half-life of diclofenac from
DICCIC (50.1 ± 17.2 min) was significantly less (Mann Whitney test, p<0.05) than that of diclofenac from diclofenac
administration (247.4 ± 100.9 min). Still the parameters clearance and distribution volume were calculated for diclofenac
from diclofenac, whose results were 9.2 ±1.2 mL/min.kg and 3.3 ±1.2 L/kg, respectively. The results of DICCIC from
DICCIC administration were 108.9 ± 19.6 mL/min.kg and 7.8 ± 2.4 L/kg for clearance and distribution volume,
respectively. The pharmacokinetic profile demonstrated that there was an increase in diclofenac elimination and a lower
exposure to diclofenac with administration of DICCIC compared to diclofenac.
Keywords: Diclofenac prodrug, 1-(2, 6-dichlorophenyl)indolin-2-one, preclinical pharmacokinetic profile, bioanalytical
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