Pharmacology of diclofenac sodium

Scholer, Dietrich W.; Ku, Edmond C.; Boettcher, I.; Schweizer, A.

doi:10.1016/0002-9343(86)90077-x

Cited by 109 publications

(50 citation statements)

References 2 publications

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“…However, this hypothesis may be reversed based on the uncertainties about the mechanism of PPAR␥ action in promoting insulin sensitivity (Miles et al, 2000;Schoonjans and Auwerx, 2000). In addition to inhibiting PPAR␥ directly, diclofenac may also diminish PPAR␥ signaling by other mechanisms, such as inhibiting cyclooxygenase (thereby decreasing the availability of endogenous prostanoid ligands that are PPAR␥ agonists) and by reducing arachidonic acid release and increasing uptake (Scholer et al, 1986). Therefore, it is a paradox that NSAIDs, such as diclofenac, might in fact promote inflammation by blocking the anti-inflammatory pathway of PPAR␥ by the three mechanisms described above.…”

Section: Discussionmentioning

confidence: 99%

Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor-γ Signaling

et al. 2002

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Although nonsteroidal anti-inflammatory drugs (NSAIDs) are used as cancer chemopreventative agents, their mechanism is unclear because NSAIDs have cyclooxygenase-independent actions. We investigated an alternative target for NSAIDs, peroxisome proliferator-activated receptor-␥ (PPAR␥), activation of which decreases cancer cell proliferation. NSAIDs have been shown to activate this receptor, but only at high concentrations. Here, we have examined binding of diclofenac to PPAR␥ using a cis-parinaric acid displacement assay and studied the effect of diclofenac effect on PPAR␥ trans-activation in a COS-1 cell reporter assay. Unexpectedly, diclofenac bound PPAR␥ at therapeutic concentrations (K i ϭ 700 nM) but induced only 2-fold activation of PPAR␥ at a concentration of 25 M and antagonized PPAR␥ trans-activation by rosiglitazone. This antagonism was overcome with increasing rosiglitazone concentrations, indicating that diclofenac is a partial agonist. No effect of diclofenac was seen without exogenous receptor, confirming that it was working through a PPAR␥-specific mechanism. This is the first description of an NSAID that can antagonize PPAR␥. In addition, this is the first time that an NSAID has been shown to bind this receptor at clinically meaningful concentrations. The physiological relevance of these findings was tested using adipocyte differentiation and cancer cell proliferation assays. Diclofenac decreased PPAR␥-mediated adipose cell differentiation by 60% and inhibited the action of rosiglitazone on the prostate cancer cell line, DU-145, allowing a 3-fold increase in proliferation. This work shows that standard doses of diclofenac may have pharmacodynamic interactions with rosiglitazone and this has therapeutic implications, both in the management of type 2 diabetes and during cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor-γ Signaling

et al. 2002

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“…It is eliminated principally by hepatic metabolism, and has analgesic, antipyretic, and anti-inflammatory properties in animals and man, making it useful in the treatment of rheumatoid arthritis, osteoarthritis [2], ankylosis and pain of varying origin, and thus treatment is not discontinued even if liver damage is present [3][4][5]. Due to the central role of the liver in the overall elimination of the majority of NSAIDs, hepatic diseases will most likely lead to a significant alteration in their pharmacokinetic behavior [6].…”

Section: Introductionmentioning

confidence: 99%

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

Reyes‐Gordillo

Muriel

Castañeda‐Hernández

et al. 2007

Biopharm & Drug Disp

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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.

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“…Diclofenac sodium (sodium-(o-[(2,6-dichlorophenyl)-amino]-phenyl)-acetate) (DS) is a non-steroidal, antiinflammatory drug characterized by a relatively low molecular weight [25,41]. It has a role in inhibiting the cyclooxygenase (COX) enzyme, reducing arachidonic acid release and improving its uptake [41].…”

Section: Discussionmentioning

confidence: 99%

Effects of diclofenac sodium on the hippocampus of rats with acute subdural hematoma: histological, stereological, and molecular approach

Türkmen¹,

Kaplan²,

Aksoy³

et al. 2016

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Pharmacology of diclofenac sodium

Cited by 109 publications

References 2 publications

Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor-γ Signaling

Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor-γ Signaling

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

Effects of diclofenac sodium on the hippocampus of rats with acute subdural hematoma: histological, stereological, and molecular approach

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Pharmacology of diclofenac sodium

Cited by 109 publications

References 2 publications

Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor-γ Signaling

Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor-γ Signaling

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

Effects of diclofenac sodium on the hippocampus of rats with acute subdural hematoma: histological, stereological, and molecular approach

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