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At least 19 recordsLinked to original sources
PubMed1993

A comparison of the efficacy of etodolac SR (Lodine SR) and etodolac (Lodine) in patients with rheumatoid arthritis or osteoarthritis.

The efficacy and safety of a sustained-release (SR) formulation of etodolac were compared with those of conventional etodolac in two separate, randomized, double-blind, multicenter, 6-week trials. This report presents an interim analysis of the data from these studies. One study included 174 patients with rheumatoid arthritis (RA): 58 received etodolac SR 400 mg once daily (q.d.), 59 received etodolac SR 600 mg q.d., and 57 received etodolac 200 mg twice daily (b.i.d.). The second study included 230 patients with osteoarthritis (OA): 80 patients received etodolac SR 400 mg q.d., 76 received etodolac SR 600 mg q.d., and 74 received etodolac 300 mg b.i.d. Efficacy was evaluated by physician's global and patient's global assessment (both studies), number of painful joints (RA study), number of swollen joints (RA study), pain intensity (OA study), and weight-bearing pain (OA study). The interim analyses of the data from the studies indicates that all three regimens produced significant improvements from baseline in all mean efficacy values at each assessment; there were no significant differences between the treatment groups. The incidence of study events, except for dyspepsia, was comparable among the treatment groups in each study; dyspepsia occurred at a significantly lower rate in patients treated with etodolac SR than in patients treated with the conventional formulation of etodolac. We conclude that etodolac SR is as effective and safe as conventional etodolac for the treatment of patients with RA or OA.

Adult↗
PubMed2006

Etodolac-liquid-filled dispersion into hard gelatin capsules: an approach to improve dissolution and stability of etodolac formulation.

The formation of melt dispersion is an effective method of increasing the dissolution rate of poorly soluble drugs, and hence, of improving the bioavailability. The carrier fusion method was used to prepare different dispersion of etodolac using Gelucire 44/14 and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). The physical characteristics of the binary systems were determined by differential scanning calorimetry (DSC), infrared spectroscopy (IR). The release rate from the resulting dispersion was determined from dissolution studies by use of USP dissolution apparatus II (paddle method). The dissolution rate of etodolac is increased in all the dispersion systems compared to that of pure drug. A liquid dispersion system of etodolac (20%) and Gelucire 44/14: TPGS blend (80%), in different ratios, was also prepared. The capsule formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. Physical and chemical properties of the dispersion didn't change during a period of storage at room temperature and at 4 degrees C, 0% RH. It was found that etodolac was chemically stable against the effects of temperature and humidity. However, the relative humidity and storage time exerted an effect on the dissolution behavior of etodolac. The changes in dissolution behavior after storage under conditions of high humidity and temperature might be related to the formation of etodolac microcrystal and to water absorption by the carrier during storage. It is predicted that acceptable shelf-lives should result when moisture-resistant packaging is used for pharmaceutical formulations of this type.

Calorimetry, Differential Scanning↗
PubMed1997

Comparison of the efficacy and safety of etodolac and piroxicam in patients with rheumatoid arthritis. Etodolac Study 326 Rheumatoid Arthritis Investigators Group.

The efficacy and safety of etodolac and piroxicam in patients with active rheumatoid arthritis were compared. A 12 week, double blind, parallel group study was conducted at 28 centers in patients 18 to 75 yrs old, randomized to receive etodolac or piroxicam. Primary efficacy criteria were investigators' and patients' global assessments and numbers of painful and swollen joints. Secondary criteria were duration of morning stiffness, grip strength, time to walk 50 feet. Westergren erythrocyte sedimentation rate (ESR), pain intensity, painful and swollen joint scores, and articular index. Of 426 patients enrolled, 140 received etodolac 200 mg bid (E200), 147 received etodolac 300 mg bid (E300), and 139 received piroxicam 20 mg qd (P20). Efficacy analyses included data from 361 patients. No significant differences occurred between the E300 and piroxicam groups in change from baseline for the primary efficacy variables. All treatments produced significant (p < 0.01) improvement from baseline in all efficacy variables, except that only E300 produced a significant decrease from baseline in ESR. No significant differences occurred in the incidence of any specific adverse event. Six patients given E200, 7 given E300, and 10 given piroxicam withdrew because of adverse reactions. The incidence of patients with hemoglobin and hematocrit results below the normal range was significantly higher for piroxicam than for either etodolac regimen. Three patients receiving piroxicam had gastrointestinal ulcers. Thus, E300 and P20 provided comparable efficacy. E200 was less effective for some variables early in the study.

Adolescent↗
PubMed2001

Isolation of an unknown metabolite of the non-steroidal anti-inflammatory drug etodolac and its identification as 5-hydroxy etodolac.

The non-steroidal anti-inflammatory drug etodolac is extensively metabolized in the liver. Renal elimination of etodolac mainly as glucuronide and its other phase I and phase II metabolites is the primary route of excretion. High-performance liquid chromatography assays of human urine after application of etodolac indicated the existence of a further monohydroxylated metabolite (metabolite X) that was identified as 5-hydroxy etodolac. For the identification, electrospray ionization mass spectrometry (ESI-MS) as well as 1H-nuclear magnetic resonance (1H-NMR) and 13C-NMR spectroscopy have been used.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Stereoselective glucuronidation and hydroxylation of etodolac by UGT1A9 and CYP2C9 in man.

1. In vitro metabolic studies with etodolac were performed. S- and R-etodolac were converted to the acylglucuronide and hydroxylated metabolites by UDP-glucuronosyltransferase (UGT) and cytochrome P450 in microsomes. However, the stereoselectivities of UGT and P450 for the isomers were opposite. S-etodolac was glucuronidated preferentially than R-etodolac by UGT. In contrast, R-etodolac was hydroxylated preferentially than S-etodolac by P450. 2. Of several human P450 enzymes, CYP2C9 had the greatest activity for hydroxylation of R-etodolac. Sulfaphenazole, an inhibitor of CYP2C9, and anti-CYP2C9 antibody inhibited the hydroxylation of R-etodolac in human liver microsomes. CYP2C9 therefore contributes to the stereoselective hydroxylation of R-etodolac. 3. Of several human UGT enzymes, UGT1A9 had the greatest activity for glucuronidation of S-etodolac. Propofol and thyroxine, inhibitors of UGT1A9, inhibited the glucuronidation of S-etodolac in human liver microsomes. Therefore, UGT1A9 is mainly responsible for the stereoselective glucuronidation of S-etodolac. 4. Because S-etodolac was metabolized more rapidly than R-etodolac in human cryopreserved hepatocytes, the stereoselectivities of UGT1A9 for etodolac substantially influenced the overall metabolism of S- and R-etodolac in man.

Animals↗
PubMed2005

Etodolac inhibits EBER expression and induces Bcl-2-regulated apoptosis in Burkitt's lymphoma cells.

Cyclooxygenase-2 (COX-2) is reported to be an important cellular target for therapy in malignancies. The growth inhibitory effects of COX-2 inhibitors on malignancies have been demonstrated to be through not only COX-2 dependent, but also independent mechanisms. In this study, we showed that etodolac, COX-2 inhibitor, induced apoptosis via COX-2 independent pathway, and investigated the molecular details of etodolac-induced apoptosis in Burkitt's lymphoma cells. In Daudi and Raji Burkitt's lymphoma cell lines, which expressed no COX-2 enzyme, etodolac more strongly induced apoptosis compared to meloxicam. Moreover, etodolac did not induce apoptosis to normal B-lymphocytes. For the pathway of etodolac-induced apoptosis, reduction of anti-apoptotic bcl-2 mRNA and Bcl-2 protein, activation of Caspase-9 and -3, down-regulation of caspase inhibitors, c-IAP-1 and Survivin were involved. Moreover, EBER-1 and -2 expression in Epstein-Barr virus positive Daudi and Raji cells were reduced to result in down-regulation of Bcl-2 by treatment with etodolac. It has been reported that etodolac has stereoisomers, R- and S-etodolac. We found that racemate of etodolac more strongly induced apoptosis in Daudi and Raji cells compared to R- or S-etodolac. In conclusion, our findings indicated etodolac inhibited EBERs expression and induced apoptosis via a Bcl-2-regulated pathway. Moreover, racemate of etodolac more effectively induced apoptosis than R- and/or S-etodolac. Therefore, these activities of etodolac potentially extend to the treatment of patients with Burkitt's lymphoma resistant to chemotherapy.

Apoptosis↗
PubMed2004

Risks of clinically significant upper gastrointestinal events with etodolac and naproxen: a historical cohort analysis.

BACKGROUND AND AIMS: Etodolac is a generic nonsteroidal anti-inflammatory drug (NSAID). Previous in vitro studies have shown that etodolac is a selective inhibitor of cyclooxygenase (COX)-2 with selectivity in between that of other COX-2 inhibitors such as celecoxib and rofecoxib. However, there are no outcomes data assessing clinically significant upper gastrointestinal (CSUGI) events with etodolac. METHODS: A historical cohort study was performed at the Dallas Veterans Affairs Medical Center in which 16,286 veteran patients (5596 patient-years) received etodolac or naproxen during a 3-year period without concurrent use of other ulcerogenic drugs other than low-dose aspirin. The primary outcome was the CSUGI event rate of the etodolac and naproxen groups without concomitant low-dose aspirin. RESULTS: The incidence of CSUGI events was .78% and .24% for naproxen and etodolac, respectively. In the NSAID-naive subset, the incidence of CSUGI events was .99% and .24% for naproxen and etodolac, respectively. Compared with naproxen, etodolac was associated with a reduction in upper gastrointestinal events, corresponding to an odds ratio of .39 (95% confidence interval, .20-.76; P = .006). Concomitantly used low-dose aspirin increased event rates with naproxen 2-fold and etodolac 9-fold. Hence, there was no significant difference in gastrointestinal event rates between etodolac and naproxen when low-dose aspirin was taken concomitantly. CONCLUSIONS: Etodolac is a generic COX-2 selective inhibitor that reduces CSUGI events compared with the nonselective NSAID naproxen. However, concomitant use of low-dose aspirin negates the gastrointestinal safety advantages of etodolac.

Adult↗
PubMed1997

Etodolac (Lodine) in the treatment of osteoarthritis: recent studies.

Etodolac (Lodine) has been marketed in the United States since 1991 for managing pain and for acute and longterm treatment of the signs and symptoms of osteoarthritis (OA). Etodolac was recently approved for the treatment of rheumatoid arthritis. We review the results of 3 recent 4 week, multicenter, placebo controlled, parallel group studies that compared the efficacy and safety of etodolac with naproxen and nabumetone. Because studies of etodolac in the treatment of OA concentrated on bid doses, the first study compared etodolac 800 mg/day given as 400 mg bid (106 patients) and 200 mg qid (105 patients) with naproxen 1000 mg/day (109 patients) and placebo (104 patients). Etodolac was as effective as naproxen, and the 2 dosage schedules of etodolac were comparable. The 2nd study compared etodolac 400 mg bid (86 patients) with naproxen 500 bid (82 patients) and placebo (86 patients). Etodolac was again found to be as effective as naproxen. The 3rd study compared etodolac 400 mg bid (91 patients) with nabumetone 1500 mg/day (89 patients) and placebo (90 patients). The results indicated that the efficacy of etodolac was comparable to that of nabumetone and resulted in significantly better scores at endpoint on the investigator's overall assessment and patient's global assessment. In all 3 studies there were no significant differences among the groups in the frequency of study events or premature discontinuations as a result of study events. The most common adverse event was digestive system disturbance, which was mild to moderate in severity. The results of these studies confirm the efficacy and safety of etodolac in managing the signs and symptoms of OA.

Administration, Oral↗
PubMedDate not supplied

Bioavailability studies with etodolac in dogs and man.

The effects of formulation, particle size, coadministration of food, antacids, or antiulcer agents on the bioavailability of etodolac (ULTRADOL, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid), a novel non-steroidal anti-inflammatory agent, have been evaluated in dogs and man. The effects of dosage regimen and/or repetitive dosing on bioavailability were also determined. In man, capsule and tablet dosage forms containing micronized etodolac were shown to have a bioavailability (AUC) equal to that of the reference etodolac solution. Etodolac from tablets and capsules was rapidly absorbed since only minor decreases in Cmax and increases in tmax were observed compared to the etodolac solution. In a comparison of regular and micronized etodolac dosage forms, both in dogs and man, similar findings, i.e. no change in AUC but small parallel changes in Cmax and tmax, were noted. Administration of etodolac with food had no effect on etodolac bioavailability in dogs but tended to cause a delay in its absorption. Coadministration of an antacid, magaldrate, or the antiulcer agent, sucralfate, had no effect on the bioavailability of etodolac in dogs, although with the latter, a significant reduction in Cmax was noted. In man, etodolac may be administered as a single bolus dose or in divided (b.i.d.) doses without any loss in bioavailability. With either regimen, on repeat administration for 7 days, no etodolac accumulation was noted.

Acetates↗
PubMed1999

Conventional and extended-release etodolac for postsurgical dental pain.

This double-masked, parallel-group, randomized study compared the analgesic efficacy and tolerability of a single investigational 1200-mg dose of extended-release etodolac with those of a single 400-mg dose of extended-release etodolac and twice-daily doses of conventional etodolac 200 and 400 mg and placebo given 8 hours apart in 237 patients with moderate or severe postoperative pain following surgical removal of > or = 2 impacted third molars. Both doses of conventional etodolac and the 1200-mg dose of extended-release etodolac were significantly more effective on all summary analgesic measures than placebo (P < 0.05). Conventional etodolac had an onset of analgesic activity within 45 (400 mg) to 60 (200 mg) minutes and an analgesic duration of 5 to 6 hours. Extended-release etodolac 1200 mg had an onset of action within 60 minutes and an analgesic duration of 12 to 24 hours. At hours 2 and 3, conventional etodolac 400 mg was significantly more effective than the other treatments; from hours 6 through 12, extended-release etodolac 1200 mg was significantly more effective than the other treatments (both, P < 0.05). No serious adverse events were observed in this study, with an incidence of side effects in the active etodolac groups no different than that with placebo. Extended-release etodolac 1200 mg has a prolonged analgesic duration and an acceptable side-effect profile in the oral surgery pain model.

Adult↗
PubMed2000

Immune hemolytic anemia caused by sensitivity to a metabolite of etodolac, a nonsteroidal anti-inflammatory drug.

BACKGROUND: Immune hemolytic anemia can be caused by sensitivity to many different drugs. In some instances, the sensitizing compound can be identified by in vitro testing, but results are often negative. One reason for this is that a drug metabolite formed in vivo can be the sensitizing agent, but the responsible metabolites have rarely been identified at a chemical level. This report describes a patient who developed severe, Coombs-positive hemolytic anemia on two occasions after taking the nonsteroidal anti-inflammatory drug etodolac. Studies were performed to characterize etodolac metabolites to which this patient was sensitive. CASE REPORT: Serum was tested for antibody in the presence and absence of drug using conventional methods and urine from individuals taking etodolac as a source of drug metabolites. Urinary metabolites of etodolac were identified by high-pressure liquid chromatography analysis. Glucuronide conjugates of etodolac and the 6-OH metabolite of etodolac were synthesized in a rat liver microsomal system to obtain reference standards. RESULTS: The patient's serum gave only trace (+/-) reactions with normal RBCs in the presence of etodolac but reacted strongly (4+) in the presence of urine from an individual taking this drug. The active urinary metabolites were identified as etodolac glucuronide and 6-OH etodolac glucuronide. CONCLUSION: This patient appears to have experienced acute, severe immune hemolytic anemia on two occasions because of sensitivity to the glucuronides of etodolac and 6-OH etodolac. In patients suspected of having drug-induced immune hemolytic anemia, RBC-reactive antibodies can sometimes be detected by using urine from an individual taking the implicated medication as the source of drug metabolites in in vitro reactions. For patients who present with acute immune hemolysis, a careful history of drug exposure should be taken, and, where indicated, confirmatory testing should be performed to identify the sensitizing drug and prevent inadvertent reinduction of hemolysis at a later time.

Acute Disease↗
PubMed1989

Etodolac, a new nonsteroidal anti-inflammatory drug: gastrointestinal microbleeding and endoscopic studies.

A review of the literature is presented on the gastrointestinal effects of etodolac, a new nonsteroidal anti-inflammatory drug (NSAID), as evaluated in both microbleeding and endoscopic studies. In four microbleeding studies, gastrointestinal blood loss in healthy subjects was estimated by a 51Cr-erythrocyte labeling method before drug treatment, after 7 days of treatment with NSAIDs including etodolac, and 1 week after the last day of treatment. In these 7-day studies, the gastrointestinal blood loss seen with etodolac (600 to 1200 mg/day) was similar to that seen with placebo and significantly (p less than 0.05) less than that seen with aspirin (2600 mg/day), naproxen (750 mg/day), ibuprofen (2400 mg/day), or indomethacin (200 mg/day). Naproxen, ibuprofen, and indomethacin caused mean daily blood losses in excess of 1 ml/day over baseline values. The increase with aspirin was 4 to 5 ml/day. In contrast, the greatest mean daily increase in blood loss with etodolac therapy was 0.2 ml. In a 4-week study of etodolac (600 and 1000 mg/day) and piroxicam (20 mg/day) given to patients with osteoarthritis or rheumatoid arthritis, blood loss seen with etodolac was comparable to that seen with placebo and significantly less than that seen with piroxicam. Gastrointestinal irritation was also assessed by endoscopy after 1 week of NSAID or placebo treatment. Endoscopy scores after etodolac treatment (up to 1200 mg/day) were similar to scores at baseline and after placebo and were significantly lower than scores following treatment with aspirin (3900 mg/day), indomethacin (200 mg/day), ibuprofen (2400 mg/day), or naproxen (100 mg/day). The effects of etodolac (600 or 1000 mg/day) and diclofenac (150 mg/day) were not different from each other or from baseline. These data indicate that etodolac, in these studies, did not cause clinically significant gastrointestinal microbleeding or visible gastric injury. By the criteria used in these studies, etodolac is less irritating to the gastrointestinal tract than aspirin, indomethacin, ibuprofen, naproxen, or piroxicam, and compares favorably with diclofenac.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Etodolac induces apoptosis and inhibits cell adhesion to bone marrow stromal cells in human myeloma cells.

OBJECTIVES: Cyclooxygenase-2 (COX-2) is reported to regulate apoptosis and to be an important cellular target for therapy. METHODS: We examined whether etodolac, meloxicam, and thalidomide inhibited proliferation and induced apoptosis in myeloma cell lines (RPMI 8226 and MC/CAR cells). RESULTS: Etodolac induced apoptosis more strongly compared with thalidomide or meloxicam. Etodolac induced down-regulation of Bcl-2 protein and mRNA, activation of Caspase-9, -7 and -3, cIAP-1 and Survivin, and loss of mitochondrial membrane potential in a dose-dependent manner. In addition, when myeloma cells were coincubated with 50 microM etodolac on bone marrow stromal cells (BMSCs), myeloma cell adhesion to BMSCs was significantly inhibited compared with thalidomide or meloxicam coincubation, and the adhesion molecules VLA-4, LFA-1 (CD11a), CXCX4, and CD44 were suppressed on myeloma cells treated with etodolac. Moreover, 50-100 microM racemate of etodolac significantly inhibited the proliferation of myeloma cells compared to 100 microM R-etodolac or S-etodolac. CONCLUSIONS: Etodolac induced loss of mitochondrial membrane potential and apoptosis via a COX-2-independent pathway, suppressed the expression of adhesion molecules, and inhibited myeloma cell adhesion to BMSCs compared with thalidomide or meloxicam. The activities of etodolac potentially extend to the treatment of patients with myeloma resistant to standard chemotherapy, including thalidomide.

Apoptosis↗
PubMed1994

Concomitant etodolac affects neither the unbound clearance nor the pharmacologic effect of warfarin.

Potential interactions between the nonsteroidal anti-inflammatory etodolac and the anticoagulant warfarin were studied in 18 healthy subjects by use of a randomized, three-period crossover design. Each treatment lasted 2 1/2 days and consisted of warfarin, etodolac, or both drugs. Prothrombin time was determined daily during each warfarin period to measure pharmacologic effect. Total serum concentration and unbound fraction of both drugs were determined over the dose interval after the last dose of the study drug(s). Concomitant etodolac did not affect the prothrombin time response or the unbound clearance of warfarin. During concomitant etodolac administration, the median peak concentration of total warfarin was significantly decreased by 19% (p = 0.005), median total clearance was significantly increased by 13% (p = 0.0123), and the unbound fraction tended to increase (median unbound fraction of warfarin, 1.245% with etodolac and 1.045% without etodolac; p = 0.0979; not statistically significant). These observations suggest a small displacement of warfarin from serum protein by etodolac or a metabolite of etodolac. No etodolac pharmacokinetic parameter was significantly affected by concomitant warfarin administration. Thus etodolac does not appear to alter the unbound clearance of warfarin or augment its pharmacologic effect. Nevertheless, it is prudent that clinical monitoring be done for individuals taking these two compounds concomitantly.

Adult↗
PubMed1994

Agranulocytosis associated with etodolac.

OBJECTIVE: To report a case of probable etodolac-induced agranulocytosis. CASE SUMMARY: A 72-year-old woman who had been taking etodolac 300 mg bid for approximately six weeks presented to the emergency department with symptoms of urosepsis. She was found to be profoundly granulocytopenic. Etodolac was discontinued and broad-spectrum intravenous antibiotic therapy was administered for the next 17 days. Results of bone marrow biopsy revealed marked hypocellularity consistent with drug-induced agranulocytosis. Following etodolac withdrawal, the total white blood cell count reached a low value of 0.9 x 10(9)/L and then returned to a pre-etodolac baseline after 15 days. Her hemoglobin concentration also decreased significantly during hospitalization. DISCUSSION: Agranulocytosis has rarely been reported in association with nonsteroidal antiinflammatory drugs (NSAIDs), and there are no literature reports associating etodolac with agranulocytosis. This case involving etodolac is consistent with the pattern described with other NSAIDs. Factors correlating etodolac as the causative agent are identified. Details of patient history, treatment, follow-up, and assessment are discussed. CONCLUSIONS: Detailed case assessment demonstrated probable etodolac-induced agranulocytosis in our patient. Clinicians should be aware that etodolac, like other NSAIDs, has potential to cause agranulocytosis.

Aged↗
PubMed1994

Etodolac clinical pharmacokinetics.

Etodolac is a chiral nonsteroidal anti-inflammatory drug (NSAID) that is marked as the racemate. Currently, the drug is available in several countries for the treatment of arthritis and the alleviation of pain. Etodolac possesses several unique disposition features mainly due to its stereoselective pharmacokinetics. In plasma, the concentrations of the 'inactive' R-enantiomer are about 10-fold higher than those of the active S-enantiomer, an observation that is novel among the chiral NSAIDs. In common with other NSAIDs, the drug is highly plasma protein bound, and undergoes virtually complete biotransformation to oxidised metabolites and acyl-glucuronides. Etodolac is well absorbed, with maximal plasma concentrations attained within 1 to 2 hours in healthy volunteers. The area under the plasma concentration-time curve of racemic etodolac increases linearly with doses used clinically. The elimination half-life of etodolac is between 6 and 8 hours in plasma, and is similar for both enantiomers. The volume of distribution (Vd) of racemic etodolac is higher than that of most other NSAIDs mainly because of the extensive distribution of the S-enantiomer. The very large Vd of the S-enantiomer, compared with its antipode is, at least in part, due to its less extensive plasma protein binding. In addition to the unchanged drug, substantial concentrations of the acyl-glucuronides of etodolac are found in both plasma and the synovial fluid of patients with arthritis. A limited amount of conjugated etodolac is found in the bile of patients following cholecystectomy. Hepatic cirrhosis has no effect on the pharmacokinetics of racemic etodolac, although the effect of hepatic dysfunction on the pharmacokinetics of the individual enantiomers has yet to be determined. In elderly non-arthritic individuals with excellent kidney function, aging does not affect the pharmacokinetics of etodolac. The pharmacokinetics of the drug in patients with renal failure have not been published, and may be important because the acyl-glucuronides are renally cleared.

Aging↗
PubMed1996

Albumin binding sites for etodolac enantiomers.

Non-steroidal anti-inflammatory drugs (NSAIDs) are strongly bound to human serum albumin (HSA), mainly to sites I and II. The aim of this study was to characterize the binding site(s) of etodolac enantiomers under physiological conditions (580 microM HSA) using equilibrium dialysis. The protein binding of etodolac enantiomers, alone or in various ratios, was studied in order to evaluate the potential competition between them. Our results showed that (S)-etodolac was more strongly bound to HSA than (R)-etodolac. The displacement of one enantiomer by its antipode was observed only at high concentrations of the competitor, and was more pronounced for (S)-form. Displacement studies of the enantiomers by specific probes of sites I and II of albumin, dansylamide, and dansylsarcosine, respectively, showed that (R)-etodolac was slightly displaced by both these probes whereas the free concentration of (S)-etodolac increased markedly in the presence of dansylsarcosine. Moreover, the binding of ligands to sites I and II is usually affected by alkaline pH, by chloride ions, and by fatty acids. For etodolac, the presence of 0.1 and 1 M chloride ions and increasing pH (5.5-9) decreased the binding of both enantiomers. The same result was obtained with addition of octanoic acid. Conversely, the addition of oleic, palmitic, or stearic acid to the protein solution increased the binding of (R)-etodolac, but decreased that of its antipode. All these findings suggest (R)- and (S)-etodolac interact mainly with site II of HSA, and that the (R)-isomer is also bound to site I under physiological conditions.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Modulation of extracellular matrix metabolism in rabbit articular chondrocytes and human rheumatoid synovial cells by the non-steroidal anti-inflammatory drug etodolac. II: Glycosaminoglycan synthesis.

The effect of Etodolac on glycosaminoglycan (GAG) synthesis by human synovial cells and rabbit articular chondrocytes in culture was studied at doses ranging from 0.01 to 10 micrograms/ml. In chondrocyte cultures, short-term exposure to Etodolac decreased the total amount of GAGs (mainly chondroitin sulfate) affecting essentially the cell layer-associated fraction. When cells were incubated with Interleukin-1 (IL-1), Etodolac still exerted its inhibiting effect on GAG synthesis. Long-term exposure of chondrocytes to Etodolac caused a diminution of the total GAG synthesis for the highest concentration studied (1 micrograms/ml). IL-1 alone or in combination with Etodolac decreased the synthesis of GAGs suggesting that pretreatment with Etodolac cannot prevent the action of IL-1. In synoviocyte cultures, the drug caused an inhibition of the GAG biosynthesis (mainly hyaluronic acid). In presence of IL-1, Etodolac at the highest concentration partially diminished the stimulatory effect of IL-1. A 8-day exposure of the cells to Etodolac led to a decrease of GAG synthesis. In the same experiment, IL-1 alone caused a slight increase of GAG production that was not abolished by Etodolac treatment.

Animals↗