title: Pharmacokinetic profile of a new diclofenac prodrug without gastroulcerogenic effect.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, Sao Paulo State University - UNESP, Rodovia Araraquara-Jau Km. 01 s/n, 14801-902 - Araraquara - Sao Paulo, Brazil. michelcampos7@yahoo.com.br
authors.forename: Michel Leandro
authors.initials: ML
authors.lastname: de Campos
authors.forename: Helen Mariana
authors.initials: HM
authors.lastname: Baldan-Cimatti
authors.forename: Marcelo Gomes
authors.initials: MG
authors.lastname: Davanco
authors.forename: Marco Antonio Ferraz
authors.initials: MA
authors.lastname: Nogueira
authors.forename: Elias Carvalho
authors.initials: EC
authors.lastname: Padilha
authors.forename: Caroline Damico
authors.initials: CD
authors.lastname: Candido
authors.forename: Jean Leandro
authors.initials: JL
authors.lastname: Dos Santos
authors.forename: Rosangela Goncalves
authors.initials: RG
authors.lastname: Peccinini
mesh_terms: D000818:Animals; D004008:Diclofenac / Q000493:pharmacokinetics / Q000633:toxicity; D007211:Indoles / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced
chemical_list: D007211:Indoles; D011355:Prodrugs; D004008:Diclofenac; C456899:1-(2,6-dichlorophenyl)indolin-2-one