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514497 
Journal Article 
Pharmacokinetics of diclofenac in rats intoxicated with CCL4, and in the regenerating liver 
Reyes-Gordillo, K; Muriel, P; Castaneda-Hemandez, G; Favari, L 
2007 
Yes 
Biopharmaceutics and Drug Disposition
ISSN: 0142-2782
EISSN: 1099-081X 
28 
8 
415-422 
English 
The pharmacokinetics of an intravenous and oral diclofenac dose of 3.2mg/kg was studied in male Wistar rats under control conditions, 1 and 3 days after liver damage and regeneration induced by an oral injection of CCI4. One day after CCI4 administration, indicators of necrosis (alanine aminotransferase), cholestasis (gamma-glutamyl transpeptidase) and regeneration (a-fetoprotein) were significantly increased; these effects were reversed after 3 days. In nonintoxicated rats, t(1/2) was 43.83 +/- 4.95 min, V-d was 0.37 +/- 0.041/kg, Cl was 129.21 +/- 9.20ml/min kg, AUC(i.v.) was 25.62 +/- 1.45 mu g/min ml, and AUC(p.o.) was 20.21 +/- 1.03. One day after intoxication, when the liver was damaged and regenerating, the metabolism was decreased: diclofenac t1/2 was increased to 258.21 +/- 30.80 min but Vd did not change significantly, therefore Cl was reduced to 32.81 +/- 3.38 ml/min kg. By day 3 after intoxication, liver function, regeneration and pharmacokinetics returned to normal. The results show that liver damage and regeneration increases the bioavailability by decreasing elimination. The present observations suggest that reduction of the pharmacokinetic parameters may lead to drug accumulation in the regenerating-damaged liver with an attendant possible increase in toxic effects. The results in rats, also suggest that once hepatic injury is finished and regeneration is complete, diclofenac can be administered normally. Copyright (0 2007 John Wiley & Sons, Ltd. 
diclofenac; liver injury; liver regeneration; carbon tetrachloride; necrosis; pharmacokinetics; clinical pharmacokinetics; carbon-tetrachloride; hepatic regeneration; alpha-fetoprotein; disease; sodium; bioavailability; binding; update; injury