Pharmacokinetics of diclofenac in rats intoxicated with CCL₄, and in the regenerating liver

Abstract

The pharmacokinetics of an intravenous and oral diclofenac dose of 3.2 mg/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 CCl(4). One day after CCl(4) administration, indicators of necrosis (alanine aminotransferase), cholestasis (gamma-glutamyl transpeptidase) and regeneration (alpha-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 +/- 0.04 l/kg, Cl was 129.21 +/- 9.20 ml/min kg, AUC(i.v.) was 25.62 +/- 1.45 microg/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 t(1/2) was increased to 258.21 +/- 30.80 min but V(d) 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.

Development of an ultra fast online-solid phase extraction (SPE) liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS) based approach for the determination of drugs in pharmacokinetic studies

“…The minimal blood volume required for analysis (10 μl) (Section 3.1) enabled sample collection by serial bleeding without disturbing the fluid balance of the animals 37. Although whole blood was used in this analysis, the results were comparable to previous observations described for plasma 38,39. After i.p.…”

“…This C max is consistent with the results from Reyes-Gordillo et al , who reported a plasma C max of about 1 μg mL −1 following i.v. administration of DCF at 3 mg kg −1 bodyweight 39. DCF is rapidly excreted, as described previously39 and after 2.4 h only half of the concentration remains in the blood.…”

“…administration of DCF at 3 mg kg −1 bodyweight 39. DCF is rapidly excreted, as described previously39 and after 2.4 h only half of the concentration remains in the blood. The animals receiving a six fold higher dose of topical DCF (6 mg kg −1 bodyweight) absorbed the compound slowly, which shifted the C max of 2713 ± 673 ng mL −1 in the blood to 1.5 h. Despite the different administration routes, the C max increased 7.4 fold with a six fold increase in dose, indicating good −1 of dose linearity.…”

Diclofenac and ketoprofen liver toxicity in rat

“…Like the other NSAIDs, the mechanism of anti-inflammatory, analgesic and antipyretic action proceeds via the inhibition of the COX enzyme, which transforms arachidonic acid to prostaglandin, prostaeyelin and thromboxane (1,2). 'Please send reprint request to: Dr Zdenko Tomic, Institute of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia zdenkoto@eunet.rs Diclofenac is metabolized in the liver by the hydroxylation at the positions 3, 4 and 5 and conjugation with glucuronic acid.…”

Pharmacokinetics and Pharmacodynamics of diclofenac in the presence and absence of glibenclamide in the rat

“…Diclofenac blood concentrations were estimated by HPLC by a procedure developed and validated in our laboratory. This method has been previously described in detail (21).…”