Propellant Free Pressurized Spray System of Etodolac to Manage Acute Pain Conditions: In Vitro and In Vivo Evaluation.

This study aimed to develop a propellant-free topical spray formulation of Etodolac (BCS-II), a potent NSAID, which could be beneficial in the medical field for the effective treatment of pain and inflammation conditions. The developed novel propellant-free spray formulation is user-friendly, cost-effective, propellant-free, eco-friendly, enhances the penetration of Etodolac through the skin, and has a quick onset of action. Various formulations were developed by adjusting the concentrations of different components, including lecithin, buffering agents, film-forming agents, plasticizers, and permeation enhancers. The prepared propellant-free spray formulations were then extensively characterized and evaluated through various in vitro, ex vivo, and in vivo parameters. The optimized formulation exhibits an average shot weight of 0.24 ± 0.30 ml and an average drug content or content uniformity of 87.3 ± 1.01% per spray. Additionally, the optimized formulation exhibits an evaporation time of 3 ± 0.24 min. The skin permeation study demonstrated that the permeability coefficients of the optimized spray formulation were 21.42 cm/h for rat skin, 13.64 cm/h for mice skin, and 18.97 cm/h for the Strat-M membrane. When assessing its potential for drug deposition using rat skin, mice skin, and the Strat-M membrane, the enhancement ratios for the optimized formulation were 1.88, 2.46, and 1.92, respectively against pure drug solution. The findings from our study suggest that the propellant-free Etodolac spray is a reliable and safe topical formulation. It demonstrates enhanced skin deposition, and improved effectiveness, and is free from any skin irritation concerns.

Pharmacokinetic modeling and simulation of etodolac following single oral administration in dogs.

Etodolac is a nonsteroidal anti-inflammatory drug with selective cyclooxygenase-2 inhibition to treat pain and inflammation associated with osteoarthritis in humans and dogs. The aim of the study was to investigate the pharmacokinetics of etodolac following single oral administration of 200 mg to 10 healthy beagle dogs. The plasma concentrations of etodolac were detected using liquid chromatography-tandem mass spectrometry. Pharmacokinetic analysis was conducted using the noncompartmental method and modeling approaches. Etodolac was rapidly absorbed (Tmax = 0.85 h, Ka = 1.49 h-1) and slowly eliminated (T1/2 = 39.55 h) following oral administration to the dogs. A two-compartment pharmacokinetic model with first-order absorption and elimination rate constants was successfully explained for the pharmacokinetic aspects of etodolac in dogs. From a Monte Carlo simulation (1000 repetitions), the accumulation index and AUCτ at steady state were predicted as 1.60 [90% confidence intervals (CI), 1.24-2.81] and 408.18 ng·hr/mL [90% CI, 271.26-590.58 ng·hr/mL], respectively. This study will help to enact a more accurate optimal dosing regimen of etodolac in dogs with osteoarthritis, and may be useful in developing a novel formulation of etodolac for human in the future.

Preparation, Characterization and In Vitro / In Vivo Evaluation of Oral Time-Controlled Release Etodolac Pellets.

The objective of this study was to prepare time-controlled release etodolac pellets to facilitate drug administration according to the body's biological rhythm, optimize the drug's desired effects, and minimize adverse effects. The preparation consisted of three laminal layers from center to outside: the core, the swelling layer, and the insoluble polymer membrane. Factors influenced the core and the coating films were investigated in this study. The core pellets formulated with etodolac, lactose, and sodium carboxymethyl starch (CMS-Na) were prepared by extrusion-spheronization and then coated by a fluidized bed coater. Croscarmellose sodium (CC-Na) was selected as the swelling agent, and ethyl cellulose (EC) as the controlled release layer. The prepared pellets were characterized by scanning electron microscopy and evaluated by a dissolution test and a pharmacokinetic study. Compared with commercial available capsules, pharmacokinetics studies in beagle dogs indicated that the prepared pellets release the drug within a short period of time, immediately after a predetermined lag time. A good correlation between in vitro dissolution and in vivo absorption of the pellets was exhibited in the analysis.

Development and in vitro/in vivo evaluation of etodolac controlled porosity osmotic pump tablets.

The aim of the current work was the design and evaluation of etodolac controlled porosity osmotic pump (CPOP) tablets exhibiting zero-order release kinetics. Variables influencing the design of (1) core tablets viz., (a) osmogent type (sodium chloride, potassium chloride, mannitol, and fructose) and (b) drug/osmogent ratio (1:0.25, 1:0.50, and 1:0.75), and (2) CPOP tablets viz., (a) coating solution composition, (b) weight gain percentage (1-5%, w/w), and (c) pore former concentration (5%, 10%, and 20%, v/v), were investigated. Statistical analysis and kinetic modeling of drug release data were estimated. Fructose-containing core tablets showed significantly (P < 0.05) more retarded drug release rates. An inverse correlation was observed between drug/fructose ratio and drug release rate. Coating of the optimum core tablets (F4) with a mixture of cellulose acetate solution (3%, w/v), diethyl phthalate, and polyethylene glycol 400 (85:10:5, v/v, respectively) till a 4% w/w weight gain enabled zero-order sustained drug delivery over 24 h. Scanning electron microscopy micrographs of coating membrane confirmed pore formation upon contact with dissolution medium. When compared to the commercial immediate-release Napilac® capsules, the optimum CPOP tablets (F4-34) provided enhanced bioavailability and extended duration of effective etodolac plasma concentration with minimum expected potential for side effects in healthy volunteers.

Enhanced Oral Bioavailability of Etodolac by the Liquisolid Compact Technique: Optimisation, In-Vitro and In-Vivo Evaluation.

BACKGROUND: Poor dissolution of Etodolac is one of the major challenges in achieving the desired therapeutic effect in oral therapy. OBJECTIVE: This study aimed to assess the potential of the liquisolid compact technique in increasing the rate of dissolution of Etodolac and thus its bioavailability. METHODS: Liquisolid compacts were prepared using PEG 400, Avicel PH-200 and Aerosil 200 as non-volatile liquid, carrier and coating material, respectively. The optimisation was carried out by applying a 32 full factorial design using Design expert software 11.0.3.0 to examine the effects of independent variables (load factor and carrier: coating ratio) on dependent variables (angle of repose and % cumulative drug release at 30 min [Q _{30 min]). Assessment of bioavailability was based on a pharmacokinetic study on rabbits and pharmacodynamics evaluation on rats, respectively. RESULTS: The formulation M3 was identified as the optimised formulation based on the better flow (lower angle of repose) and a higher rate of dissolution (Q 30 min >95%). The higher dissolution rate could be due to conversion of Etodolac into an amorphous molecularly dispersed state, availability of larger surface area, enhancement of aqueous solubility and enhanced wetting of drug particles. Studies with DSC, XRD, and SEM verified the transformation of Etodolac from crystalline to amorphous state, a key factor responsible for improving the dissolution rate. The pharmacokinetic profile of M3 was prominent, demonstrating higher absorption of Etodolac in comparison to oral suspension and immediate-release conventional tablets in rabbits. Liquisolid formulation exhibited a 27% increment in paw thickness as compared to 57% and 46% increments for oral suspension and immediate-release conventional tablets, respectively, after 7 hrs in the carrageenan-induced paw model in rats. CONCLUSION: The results indicated the liquisolid compact technique to be a promising strategy to enhance the bioavailability of Etodolac.}

Polymeric surfactant based etodolac chewable tablets: formulation and in vivo evaluation.

Etodolac (ET) is a nonsteroidal anti-inflammatory drug with proved potential antitumor and uric acid lowering effects. It shows dissolution rate-dependent bioavailability. This work was carried out to improve the dissolution rate of etodolac using three carriers of known potential to improve solubility and hence dissolution rate of poorly soluble drugs through coevaporation technique. The polymeric surfactant inutec, 2-hydroxypropyl-ß-cyclodextrin, and tromethamine were used at three different drug/carrier ratios. The dissolution rate of ET at pH 1.2 and 6.8 is improved in all of the solid dispersion systems compared to that of the pure drug and physical mixtures. DSC of coevaporates at 1:5 drug/carrier ratio providing the fastest dissolution rate suggested loss of ET crystallinity which was further confirmed by X-ray diffraction. Inutec-based coevaporate was chosen for the formulation of ET chewable tablets. Chewable tablets (F3) that met the USP monograph specifications for ET tablets, with 86% dissolved amount within 15 min, was chosen for in vivo absorption study in comparison with pure ET-filled hard gelatin capsules. The results showed significantly higher mean C (max) and shorter mean T (max) (about 2 h earlier) and about 1.32-fold higher mean AUC(0-24) values for the F3 chewable tablets compared to ET-filled capsules.

In vitro and ex vivo permeation studies of etodolac from hydrophilic gels and effect of terpenes as enhancers.

Etodolac, a highly lipophilic anti-inflammatory drug, is widely used in rheumatoid arthritis usually at an oral dose of 200 mg twice daily. The commonest side effects during therapy with etodolac is generally gastrointestinal disturbances these are usually mild and reversible but in some patients are peptic ulcer and severe gastrointestinal bleeding. To eliminate these side effects and obtain high drug concentration at the application side, dermal application of etodolac seems to be an ideal route for administration. Hydrophilic gel formulations of etodolac were prepared with carboxymethylcellulose sodium. The effect of different terpenes (anethole, carvacrol, and menthol) as an enhancer on the percutaneous absorption of etodolac was also investigated. Permeation studies were carried out with unjacketed modified horizontal diffusion cells through cellulose membrane and rat skin. In vitro studies with cellulose membrane showed that all formulations presented the same drug release profile (p > 0.05). Ex vivo studies with excised rat skin revealed that etodolac was released and penetrated into rat skin quickly. Anethole, a hydrophobic terpene, enhanced the absorption of etodolac significantly (p < 0.05). This result is consistent with the fact that hydrophobic terpenes are effective on the percutaneous absorption of lipophilic drugs. Menthol and carvacrol, hydrophilic terpenes, did not enhance the absorption of etodolac. The lipophilicity of the enhancers seems an important factor in promoting penetration of etodolac through the skin. Since etodolac creates gastrointestinal disturbances, topical formulations of etodolac in gel form including 1% anethole could be an alternative.

Etodolac transdermal cubosomes for the treatment of rheumatoid arthritis: ex vivo permeation and in vivo pharmacokinetic studies.

In this study, transdermal etodolac-loaded cubosomes were developed in order to relieve patient pain and joints stiffness by providing stable etodolac concentration at the targeting sites through controlled drug delivery via the noninvasive skin route with more sustaining and less frequent dosing. Different ratios and percentages of poloxamer 407 and monoolein were used to formulate the cubosomes using emulsification and homogenization processes. The etodolac-loaded cubosomes showed particle size values ranging from 135.95 to 288.35 nm and zeta potential values ranging from -18.40 to -36.10 mV. All the cubosomes offered an encapsulation efficiency value of about 100% and showed drug loading capacity ranging from 1.28 to 6.09%. The in vitro drug release studies revealed a controlled drug release profile with a drug release rate up to 15.08%/h. Increasing poloxamer concentration in etodolac-loaded cubosomes resulted in nanoparticles with less particle size and faster drug release. The particles exhibited cubic and hexagonal shapes. The DSC and X-ray analysis demonstrated that the drug was encapsulated in the cubosomes bicontinuous structures in amorphous form. In addition, investigated cubosomes exhibited fast drug penetration through excited mice skin followed by slower drug penetration for up to 24 h. The pharmacokinetic study in human volunteers showed that the selected etodolac-loaded cubosomes enhanced the bioavailability of etodolac as compared to the oral capsules (266.11%) with evidence of longer half-life and higher MRT that reached 18.86 and 29.55 h, respectively. The etodolac-loaded cubosomes propose a promising system for treatment of arthritis simply through skin application.

Development of an Enantioselective and Biomarker-Informed Translational Population Pharmacokinetic/Pharmacodynamic Model for Etodolac.

Cyclooxygenase-2 (COX-2) isoform has a critical role in the development of pain. Inhibition of COX-2 in vitro serves as a biomarker for nonsteroidal anti-inflammatory drugs (NSAIDs). The NSAID concentrations yielding 80% COX-2 inhibition (IC80) correlate with therapeutic doses to achieve analgesia across multiple COX-2 inhibitors. However, there are no time-course models relating COX-2 inhibition with decreased pain. This study aimed to characterize the relationship between NSAID concentrations, in vitro COX-2 inhibition, and acute pain decrease in humans over time by a translational approach using clinical pharmacokinetic and literature reported in vitro and clinical pharmacodynamic data. In a two-way cross-over study, eight healthy volunteers received 300 and 400 mg racemic etodolac, a preferential COX-2 inhibitor. R- and S-etodolac were determined by LC-MS/MS and simultaneously modeled. Literature in vitro IC50 data for COX-2 inhibition by S-etodolac were used to fit adjusted pain score profiles from dental patients receiving etodolac. External model qualification was performed using published ibuprofen data. Etodolac absorption was highly variable due to gastric transit kinetics and low aqueous solubility. The disposition parameters differed substantially between enantiomers with a total clearance of 2.21 L/h for R-etodolac and 26.8 L/h for S-etodolac. Volume of distribution at steady-state was 14.6 L for R-etodolac and 45.8 L for S-etodolac. Inhibition of COX-2 by 78.1% caused a half-maximal pain decrease. The time-course of pain decrease following ibuprofen was successfully predicted via the developed translational model. This proposed enantioselective pharmacodynamic-informed approach presents the first quantitative time-course model for COX-2 induced pain inhibition in patients.

Quantification of Etodolac in Human Plasma for Pharmacokinetics and Bioequivalence Studies in 27 Korean Subjects.

OBJECTIVE: We developed a simple and validated liquid chromatography tandem mass spectrometry( LC-MS/MS) for quantification of etodolac using pioglitazone as an internal standard (IS) to assess pharmacokinetics and to appraise bioequivalence of two formulations of etodolac (reference and tested) in 27 healthy Korean subjects. METHODS: Isocratic mobile phase consisted of 10 mM ammonium formate and acetonitrile were used to separate the analytes on a Gemini C18 column. Also, analytes were analyzed by MS/MS in multiple reaction monitoring (MRM) mode using the transitions of (M+H)+ ions, m/z 288.2→ 172.3 and m/z 357.1→ 134.2 for quantification of etodolac and IS each. The standard calibration curves displayed significant linearity within the range of 0.2-30.0 µ g/mL (r2=0.9956, 1/x2 weighting) with LLOQ of 0.1 µg/mL. RESULTS: The retention times of etodolac and the IS were 0.77 min and 0.57 min each, indicating the high-throughput potential of the proposed method. The pharmacokinetic parameters were calculated from the plasma samples and data form the reference and test drugs were represented as follows; Area under plasma concentration-time curve (AUCt) (78.03 vs. 84.00 µgxh/mL), AUC∞ (86.67 vs. 93.92 µgxh/mL), maximal plasma concentration (Cmax) (19.49 vs. 18.94 µg/mL), time for maximal concentrations (Tmax) (2.13 vs. 2.26 h), Plasma elimination half-life (T1/2) (8.12 vs. 8.47 h), elimination rate constant (λz) (0.0853 vs. 0.0818 h-1). Pharmacokinetic parameters with 90% confidence interval fall within the bioequivalence range of 80-125%. CONCLUSION: Thus, the new testified method was successfully applied for the pharmacokinetic and bioequivalence studies for two etodolac formulations.

Nonsteroidal antiinflammatory drugs: a review.

The increasing use of nonsteroidal antiinflammatory drugs (NSAIDs) in small animals has resulted in the development of new and innovative additions to this class of drugs. Examples of NSAIDs now available for use in small animals include aspirin, etodolac, carprofen, ketoprofen, meloxicam, deracoxib, and tepoxalin. The purposes of this article are to review the pathophysiology of prostaglandin synthesis and inhibition, the mechanisms of action, pharmacokinetics, pharmacological effects, and potential adverse reactions of aspirin and the newly released NSAIDs.

An ionic liquid-in-water microemulsion as a potential carrier for topical delivery of poorly water soluble drug: Development, ex-vivo and in-vivo evaluation.

In this paper, we report an ionic liquid-in-water (IL/w) microemulsion (ME) formulation which is able to solubilize etodolac (ETO), a poorly water soluble drug for topical delivery using BMIMPF6 (1-butyl-3-methylimidazolium hexafluorophosphate) as IL, Tween 80 as surfactant and ethanol as co-surfactant. The prepared ME was characterized for physicochemical parameters, subjected to ex-vivo permeation studies as well as in-vivo pharmacodynamic evaluation. The ex-vivo drug permeation studies through rat skin was performed using Franz-diffusion cell and the IL/w based ME showed maximum mean cumulative percent permeation of 99.030±0.921% in comparison to oil-in-water (o/w) ME (61.548±1.875%) and oily solution (48.830±2.488%) of ETO. In-vivo anti-arthritic and anti-inflammatory activities of the prepared formulations were evaluated using different rodent models and the results revealed that ETO loaded IL/w based ME was found to be more effective in controlling inflammation than oily solution, o/w ME and marketed formulation of ETO. Histopathological studies also demonstrated that IL/w based ME caused no anatomical and pathological changes in the skin.

Chiral bioequivalence: effect of absorption rate on racemic etodolac.

BACKGROUND: For many racemic drugs, bioequivalence assessment based on isomer-nonspecific assays is appropriate because enantiomeric area under the concentration-time curve (AUC) exposure ratios are close to unity. Use of nonspecific methods in cases in which the ratio is substantially greater or less than 1, however, may obscure real therapeutic differences among formulations, especially if the enantiomers exhibit differing pharmacological potencies. OBJECTIVE: To examine the influence of absorption rate on etodolac bioequivalence as measured by total [(R,S)-] and (S)-etodolac. DESIGN: Single dose, 3-period, crossover, pharmacokinetic study in 24 healthy volunteers in which the administration rate of etodolac was varied. METHODS: Participants received etodolac 400mg in solution, given as a single dose over 1 minute or as divided doses over 30 and 90 minutes. Unresolved and enantiomer concentrations of etodolac were measured by a validated HPLC assay. The enantiomer ratio was similarly measured by HPLC. RESULTS: Bioequivalence parameters derived for both unresolved and (S)etodolac indicate that peak plasma drug concentration (Cmax) was not bioequivalent. By delaying absorption, bioequivalence was lost. CONCLUSIONS: Collectively, these data demonstrate that bioequivalence between 2 products of etodolac based on enantiomerically nonspecific criteria alone may not generalise to the pharmacologically relevant (S)-enantiomer. This suggests that enantiospecific assays are necessary for bioequivalence assessments.

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.

The stereoselective pharmacokinetics of etodolac in young and elderly subjects, and after cholecystectomy.

The pharmacokinetics of the enantiomers of etodolac were studied in six young subjects (ages 28 +/- 3.3 years), 6 nonarthritic elderly subjects (ages 73 +/- 6.0 years), and in three cholecystectomy patients after single oral doses of the racemate (200 mg). In all subjects, the plasma concentrations of R-etodolac, which is pharmacologically inactive, greatly exceeded those of the pharmacologically active S-enantiomer. Stereoselectivity was reflected in the pharmacokinetics, with R > S for maximum peak plasma concentration and area under the concentration versus time curve, and S > R for apparent oral clearance and apparent volume of distribution. On average, less than 25% of the dose of each enantiomer was excreted in the urine within 24 hours as alkali-labile conjugates; little or no unchanged drug was recovered. Bile constituted a minor route of elimination of etodolac as conjugated enantiomers. There were no significant differences in the pharmacokinetics of etodolac enantiomers between the young and elderly subjects. The results reflect the importance of considering stereoselectivity in evaluating the pharmacokinetics of etodolac.

Pharmacokinetic and pharmacodynamic action of etodolac in patients after oral surgery.

The objective of this double-blind, randomized, parallel-group study was to evaluate the pharmacokinetics of etodolac and the pharmacodynamic response of pain in patients following oral surgery who had received 200 or 400 mg of etodolac immediate release (IR), 400 or 1200 mg of etodolac extended release (ER), or a placebo. Etodolac concentrations in 441 plasma samples from 187 patients were analyzed for population pharmacokinetics using the NONMEM program. A one-compartment pharmacokinetic model with first-order absorption described the observed data. For etodolac IR, the population mean (%CV) estimates were 3.01 L/h (5.3%) for clearance, 13.6 L (6.8%) for volume of distribution, and 2.31 h-1 (33%) for ka. Respective values for etodolac ER were 3.68 L/h (11%) for clearance, 24.3 L (22%) for volume of distribution, and 0.172 h-1 (24%) for ka. These values generally agreed with previously reported values in healthy adults. Pharmacodynamic assessments included collection of a four-level categorical rating of pain intensity for up to 24 hours after treatment. Pain intensity difference scores were temporally related to etodolac concentrations and were described using an indirect response model. Mean (%CV) pharmacodynamic parameters were IC50 of 14.0 mg/L (9.5%), kout of 1.62 h-1 (13%), FR of 0.56 (8.2%), and Hill coefficients that ranged from 1.26 to 3.34 units. A single 1200 mg dose of etodolac ER given once daily was shown to provide substantial efficacy for 13 hours after dose, modest effect through 24 hours, and a more sustained duration of action than the IR dosage form.

Pharmacokinetics of etodolac in patients with stable juvenile rheumatoid arthritis.

This was a single-center, open-label, single-dose pharmacokinetic study of etodolac in pediatric and adolescent patients with stable juvenile rheumatoid arthritis (JRA). Eleven male and female patients with JRA (8.1 to 14.8 years of age, weighing 26.4 to 59.5 kg) received a single oral dose of etodolac (200, 300, or 400 mg based on body weight). Clinical laboratory measurements, measurement of vital signs, and physical examinations were performed to monitor safety. Concentrations of etodolac were determined in plasma using high-performance liquid chromatography with ultraviolet detection with a limit of quantitation of 0.2 mg/L and were analyzed using a noncompartmental pharmacokinetic method. Pharmacokinetic parameters observed were consistent in magnitude and degree of variability with data from healthy adult subjects receiving a single 400- or 600-mg dose of etodolac. Although the mean fraction of unbound drug in patients with JRA was higher than in healthy adults, the oral clearance was independent of age. No serious adverse events occurred during this study. Etodolac yielded consistent pharmacokinetic values among stratified dose subgroups. Single doses of all etodolac treatments were well tolerated in both pediatric and adolescent patients.

Site-specific drug delivery in the dog using flexible fiberoptic endoscopy.

The development of a nonsurgical repeatable method of site-specific delivery to the gastrointestinal tract in the canine is described. Studies to characterize and validate this method were performed utilizing propranolol and etodolac due to their well-known pharmacokinetic properties. Using a catheter placed through the auxiliary port of a flexible fiberoptic endoscope, liquid dosage formulations were consistently delivered to the canine stomach, duodenum, ileum, and colon. It was shown that differences in site-specific delivery could be demonstrated with this model. Propranolol tended to have the highest exposure following dosing to the ileum as compared to other sites. The anesthetic regimen used to perform endoscopy affected certain pharmacokinetic parameters of the compounds being tested including decreasing the intrinsic clearance of propranolol. However, since decreased intrinsic clearance should similarly affect AUCo regardless of the site of delivery, this does not preclude site-specific comparisons to be made. Further, no evidence has been reported for the effect of anesthesia on one GI segment but not another. Thus for other compounds, assuming there are either no anesthetic effects on intestinal pharmacokinetic parameters (absorption, intestinal metabolism, etc.) or that they are consistent and uniform throughout the intestinal tract, this model allows comparisons of the exposure following delivery to differing intestinal sites.

Bioavailability and bioequivalence of two formulations of etodolac (tablets and suppositories).

We studied the influence of administration route on the biopharmaceutical behavior of etodolac. The levels obtained in plasma when the same dose of etodolac is administered orally (tablets, dosage form A) and rectally (suppositories, dosage form B) were compared. The study was done in a crossover design with healthy volunteers of both sexes, of average build, and younger than 35 years of age. From the concentration in plasma-time data, the maximum concentration in plasma (Cmax), time to Cmax, and area under the curve up to the last measurable concentration (AUC0t) or infinity (AUC 0 infinity) were calculated and compared by analysis of variance. With the exception of Cmax, no significant differences between treatments were found in the rest of the parameters. Finally, with formulation A (tablets) as a reference, the relative bioavailability was established, on the basis of the ratio (B:A) of AUC0t and AUC 9 infinity, within the range 100 +/- 20%. The results indicate that the two routes of administration are bioequivalent and that the rectal route is an alternative administration route for etodolac.

Etodolac in equine urine and serum: determination by high-performance liquid chromatography with ultraviolet detection, confirmation, and metabolite identification by atmospheric pressure ionization mass spectrometry.

A high-performance liquid chromatographic method was used for the detection of etodolac in equine serum and urine. The method consisted of a one-step liquid-liquid extraction, separation on a reversed-phase (RP-18) column and detection using an ultraviolet detector. Additional confirmation methods included a HPLC coupled with an atmospheric pressure chemical ionization mass spectrometer (APCI-MS). Free (unbound) etodolac and its conjugates were present in the samples. Concentrations of the drug in the serum and urine samples collected from four standardbred mares after a single oral administration of Ultradol were determined. Maximum etodolac concentrations of 712, 716, 568, and 767 microg/mL in urine and 4.1, 3.6, 3.1, and 2.2 microg/mL in serum were observed. The peak concentrations of the drug were detected 2-10 h (urine) and 40 min-6 h (serum) after administration to four horses. The maximum detection time was 79 h in urine and 48 h in serum after the drug administration. The drug-elimination profiles for both urine and serum are presented and discussed. Method ruggedness and precision and stability studies of etodolac in serum and urine are presented. Three major metabolites were detected in the urine by liquid chromatography-APCI-MS. All three metabolites were identified as monohydroxylated etodolac.