Inhibitory Effects Of Diclofenac Research Articles

Inhibitory Effects of Diclofenac on Steroid Glucuronidation In Vivo Do Not Affect Hair-Based Doping Tests for Stanozolol.

In vitro studies show that diclofenac inhibits enzymatic steroid glucuronidation. This study was designed to investigate the influence of diclofenac on the excretion of stanozolol and 3′-hydroxystanozolol via analyses in hair, blood and urine in vivo in a rat study. Brown Norway rats were administered with stanozolol (weeks 1–3) and diclofenac (weeks 1–6). Weekly assessment of steroid levels in hair was complemented with spot urine and serum tests. Levels of both stanozolol and 3′-hydroxystanozolol steadily increased in hair during stanozolol treatment and decreased post-treatment, but remained readily detectable for 6 weeks. In contrast, compared to control rats, diclofenac significantly reduced urinary excretion of 3′-hydroxystanozolol which was undetectable in most samples. This is the first report of diclofenac altering steroid metabolism in vivo, detrimentally affecting detection in urine, but not in hair, which holds considerable advantages over urinalysis for anti-doping tests.

Drug interactions of diclofenac and its oxidative metabolite with human liver microsomal cytochrome P450 1A2-dependent drug oxidation

1. The purpose of this study was to investigate the inhibitory effects of diclofenac on human cytochrome P450 1A2-, 2C19- and 3A4-mediated drug oxidations and to evaluate the drug interaction potential of diclofenac and 4′-hydroxydiclofenac.2. Diclofenac was converted to 4′-hydroxydiclofenac by recombinantly expressed human P450 1A2 with Km and Vmax values of 33 µM and 0.20 min−1, respectively. Diclofenac and 4′-hydroxydiclofenac suppressed flurbiprofen 4′-hydroxylation by P450 2C9 strongly and moderately, respectively; however, they did not affect P450 2C19-dependent S-mephenytoin hydroxylation or P450 3A4-dependent midazolam hydroxylation.3. Although the caffeine 3-N-demethylation activity of liver microsomal P450 1A2 was inhibited by simultaneous incubation with diclofenac, the riluzole N-hydroxylation activities of recombinant P450 1A2 and human liver microsomes were inhibited after preincubation with diclofenac or 4′-hydroxydiclofenac for 20 min in the presence of NADPH. Using the inhibition constant (37 µM) of diclofenac on caffeine 3-N-demethylation and the reported 95th percentiles of maximum plasma concentration (10.5 µM) after an oral dose of diclofenac, the in vivo estimated increase in area under the plasma concentration–time curve was 29%.4. These results suggest that diclofenac could inhibit drug clearance to a clinically important degree that depends on P450 1A2. Clinically relevant drug interactions in vivo with diclofenac are likely to be invoked via human P450 1A2 function in addition to those caused by the effect of diclofenac on P450 2C9.

The non-steroidal anti-inflammatory drug, diclofenac, inhibits Na + current in rat myoblasts

The inhibitory effect of diclofenac, a non-steroidal anti-inflammatory drug (NSAID), on the voltage-gated inward Na + current ( I Na) in cultured rat myoblasts was investigated using the whole-cell voltage-clamp technique. At concentrations of 10 nM–100 μM, diclofenac produced a dose-dependent and reversible inhibition of I Na with an IC 50 of 8.51 μM, without modulating the fast activation and inactivation process. The inhibitory effect of diclofenac took place at resting channels and increased with more depolarizing holding potential. In addition to inhibiting the Na + current amplitude, diclofenac significantly modulated the steady-state inactivation properties of the Na + channels, but did not alter the steady-state activation. The steady-state inactivation curve was significantly shifted towards the hyperpolarizing potential in the presence of diclofenac. Furthermore, diclofenac treatment resulted in a fairly slow recovery from inactivation of the Na + channel. The inhibitory effect of diclofenac was enhanced by repetitive pulses and was inflected by changing frequency; the blocking effect at higher frequency was significantly greater than at lower frequency. Both intracellular and extracellular application of diclofenac could inhibit I Na, indicating that diclofenac may exert its channel inhibitory action both inside and outside the channel sites. Our data directly demonstrate that diclofenac can inhibit the inward Na + channels in rat myoblasts. Some different inhibitory mechanisms from that in neuronal Na + channels are discussed.

Lack of influence of the COX inhibitors metamizol and diclofenac on platelet GPIIb/IIIa and P-selectin expression in vitro.

BackgroundThe effect of non-steroidal anti-inflammatory drugs (NSAIDs) for reduced platelet aggregation and thromboxane A2 synthesis has been well documented. However, the influence on platelet function is not fully explained. Aim of this study was to examine the influence of the COX-1 inhibiting NSAIDs, diclofenac and metamizol on platelet activation and leukocyte-platelet complexes, in vitro. Surface expression of GPIIb/IIIa and P-selectin on platelets, and the percentage of platelet-leukocyte complexes were investigated.MethodsWhole blood was incubated with three different concentrations of diclofenac and metamizol for 5 and 30 minutes, followed by activation with TRAP-6 and ADP. Rates of GPIIb/IIIa and P-selectin expression, and the percentage of platelet-leukocyte complexes were analyzed by a flow-cytometric assay.ResultsThere were no significant differences in the expression of GPIIb/IIIa and P-selectin, and in the formation of platelet-leukocyte complexes after activation with ADP and TRAP-6, regarding both the time of incubation and the concentrations of diclofenac and metamizol.ConclusionsAccordingly, the inhibitory effect of diclofenac and metamizol on platelet aggregation is not related to a reduced surface expression of P-selectin and GPIIb/IIIa on platelets.

Diclofenac inhibition of sodium currents in rat dorsal root ganglion neurons

The effects of diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), on the fast tetrodotoxin-sensitive (TTX-S) and the slow tetrodotoxin-resistant (TTX-R) sodium currents in rat dorsal root ganglion neurons were investigated using the whole-cell patch-clamp method. Diclofenac suppressed both sodium currents in a dose-dependent manner. The apparent dissociation constants for the diclofenac suppression of TTX-S and TTX-R sodium currents were estimated to be 14 and 97 μM, respectively, at a holding potential of −80 mV. Diclofenac had no effect on the kinetic parameters of the activation process in either type of sodium current. However, diclofenac produced shifts of the steady-state inactivation curves in the hyperpolarizing direction in both types of sodium currents in a dose-dependent manner. At sufficiently negative holding potentials, the inhibitory effects of diclofenac on both types of sodium currents were minimal. The results suggested that diclofenac might bind to sodium channels with a greater affinity when they are in the inactivated state than when they are in the resting state. Effects of other NSAIDs (acetylsalicylic acid, antipyrin, indomethacin and flufenamic acid) on sodium currents were tested. Among these, only flufenamic acid suppressed the sodium currents to a considerable extent. Thus, the chemical structure of each NSAID, not the inhibition of cyclooxygenase, seems to be an important determinant in the sodium current inhibition. The suppression of sodium currents in sensory neurons by diclofenac and flufenamic acid would contribute to their analgesic activity in addition to their inhibition of cyclooxygenase.

Inhibitory effects of diclofenac on the endotoxin shock response in relation to endothelin turnover in the pig

During sepsis vasoactive arachidonic acid metabolites of the cyclo-oxygenase pathway and the endothelium-derived vasoconstrictor endothelin-1 (ET-1) are released. The effects of cyclo-oxygenase pathway inhibition by diclofenac on the endotoxin shock response and ET-1 turnover, were investigated in five groups of pigs. In the first group (n = 7; controls) endotoxin (15 micrograms.kg-1.h-1 i.v.) was infused for two hours. In a second endotoxin group (n = 7), the animals were pretreated with diclofenac (3 mg.kg-1 i.v.). In a third group (n = 7), high-dose ET-1 was infused (20 pmol.kg-1.min-1 i.v.) and in a fourth group (n = 7), the ET-1 infusion was preceded by diclofenac. In a fifth group (n = 4), a low and intermediate dose of ET-1 (0.2 and 4 pmol.kg-1.min-1) was infused. A significant increase in ET-1-like immunoreactivity (LI) plasma levels was observed in both endotoxin groups, but in the diclofenac group the increase was comparatively delayed. Furthermore, this group showed a more stable haemodynamic course and in the biphasic increase of pulmonary vascular resistance seen in endotoxin controls, the initial peak was abolished by diclofenac. Exogenous ET-1 infusion indicated that not only locally released but possibly also circulating ET-1 could be a mediator of vascular responses to endotoxin. Indications of release from the lungs were seen during endotoxin infusion. Diclofenac had no effect on basal ET-1-LI plasma levels or on the disappearance rate from plasma of ET-1-LI and the haemodynamic changes seen on ET-1 infusion. The inhibition of cyclo-oxygenase pathway by diclofenac resulted in prevention of the initial pulmonary hypertension and a delayed increase in plasma ET-1-LI levels in porcine endotoxin shock and this latter effect is not due to an increased rate of disappearance from plasma but rather to a decreased release of ET-1.

Effect of diclofenac on fixation of hydroxyapatite-coated implants. An experimental study

We studied the effect of non-steroidal anti-inflammatory drugs on the fixation of hydroxyapatite-coated implants. Cylindrical plugs of pure titanium, coated with hydroxyapatite (HA), were inserted into both femora of 10 adult rabbits, 5 of which received 7 daily doses of 30 mg diclofenac. Three weeks after implantation the interface strengths were measured by the pull-out test. The mean peak force for the diclofenac-treated group was 290 +/- 57 N compared with 369 +/- 37 N for the control group (p < 0.025). We conclude that the inhibitory effect of diclofenac on bone repair is not neutralised by HA-coating of an implant.

Inhibitory effects of diclofenac and indomethacin on interleukin-1-induced changes in PGE 2 release : A novel effect on free arachidonic acid levels in human synovial cells

The inhibitory effects of two non-steroidal anti-inflammatory drugs (NSAIDS), diclofenac and indomethacin, on interleukin-1 (IL-1)-induced changes in arachidonic acid (AA) release and prostaglandin E 2(PGE 2) production by human synovial cells was investigated. Both diclofenac and indomethacin potently inhibited IL-1α-induced PGE 2 release, with ic 50 values of 1.6 ± 0.02 nM and 5.5 ± 0.1 nM, respectively. A novel effect on IL-1α-mediated changes in AA levels was observed using cells labelled with radioactive AA. Both drugs at micromolar concentrations (10–30 μM) showed an apparent inhibition of IL-1α-induced increases in radioactivity associated with free AA. Concomitant with this inhibition, there was an increase in radioactivity associated with phosphatidylethanolamine (PE) and triglyceride (TG). As the drugs had no effect on IL-1α-induced decreases in radioactivity associated with phosphatidylcholine (PC), this result was interpreted as being due to an enhanced acylation of AA into PE and TG. These results suggest that whilst at nanomolar concentrations, diclofenac and indomethacin can inhibit IL-1α-induced PGE 2 output, at micromolar concentrations an effect on free AA levels is also evident. This may have consequences for the release of other mediators such as leukotrienes, whose synthesis also involves the level of free AA.