Pharmacokinetic Profile of A New Diclofenac Prodrug without Gastroulcerogenic Effect
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2013-03-01
Autores
de Campos, Michel Leandro [UNESP]
Baldan-Cimatti, Helen Mariana [UNESP]
Davanço, Marcelo Gomes [UNESP]
Nogueira, Marco Antônio Ferraz [UNESP]
Padilha, Elias Carvalho [UNESP]
Candido, Caroline Damico [UNESP]
dos Santos, Jean Leandro [UNESP]
Peccinini, Rosangela Goncalves [UNESP]
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Resumo
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. © 2013 Bentham Science Publishers.
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Palavras-chave
1-(2,6-dichlorophenyl)indolin-2-one, Bioanalytical method, Diclofenac prodrug, Preclinical pharmacokinetic profile, [1 (2,6 dichlorophenyl)indolin 2 one], diclofenac, diclofenac derivative, prodrug, unclassified drug, allometry, animal experiment, area under the curve, controlled study, distribution volume, drug clearance, drug determination, drug distribution, drug elimination, drug exposure, drug half life, high performance liquid chromatography, limit of quantitation, male, nonhuman, pharmaceutical equivalence, plasma concentration-time curve, priority journal, rat
Como citar
Drug Metabolism Letters, v. 6, n. 4, p. 235-241, 2013.