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Toxicological detection of ibuprofen and its metabolites in urine using gas chromatography-mass spectrometry (GC-MS).

Maurer HH, Kraemer T, Weber A.

Institut fur Pharmakologie und Toxikologie, Universitat des Saarlandes, Homburg, Saar.

Ibuprofen, (R,S)-2-(4-isobutylphenyl)propionic acid, is a non-opioid analgesic which is prescription-free available in pharmacies since 1989. Consequently, use and misuse of this analgesic strongly increased. For diagnosis of an abuse or an intoxication a GC-MS procedure was developed for the toxicological detection of ibuprofen in urine after extraction at pH 5 and methylation. For screening, mass chromatography with the masses m/z 220, 161 (methylated ibuprofen), 178, 119 (methylated hydroxy ibuprofen) and 264, 145 (methylated carboxy ibuprofen) was used to indicate the presence of these compounds in urine. The identity of the peaks underlying full mass spectra was confirmed by comparison with the reference spectra using computer library search. After ingestion of one single oral dose of 400 mg ibuprofen, the parent compound could be detected for 27 to 34 h, hydroxy ibuprofen for 34 to 40 h and carboxy ibuprofen for 5 to 6 d. Using this procedure ibuprofen which was taken even several days ago could be detected.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8171078&dopt=Abstract ibuprofen Motrin



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Induction of hepatic microsomal CYP4A activity and of peroxisomal beta-oxidation by two non-steroidal anti-inflammatory drugs.

Rekka E, Ayalogu EO, Lewis DF, Gibson GG, Ioannides C.

Division of Toxicology, School of Biological Sciences, University of Surrey, Guildford, UK.

The effects of the non-steroidal anti-inflammatory drugs fenbufen and ibuprofen on hepatic cytochrome P450 activities and peroxisomal proliferation were investigated in the rat, following intraperitoneal administration at three dose levels. At the two highest doses, 30 and 150 mg/kg, ibuprofen stimulated lauric acid hydroxylase activity but no other dose-dependent effects on cytochrome P450 activities were evident. Fenbufen, at the highest dose of 150 mg/kg, decreased cytochrome P450 content and related activities, and this effect was attributed to the toxicity of the drug at this dose. Immunoblot studies employing solubilized microsomes from ibuprofen-treated rats revealed that ibuprofen increased the apoprotein levels of CYP4A1, at the two higher doses. The same treatment with ibuprofen, at the highest dose only, increased the beta-oxidation of palmitoyl CoA, determined in liver homogenates, and immunoblott analysis showed an increase in the apoprotein levels of the trans-2-enoyl CoA hydratase trifunctional protein. Fenbufen did not influence palmitoyl beta-oxidation. Computer graphic overlays with clofibric acid showed that ibuprofen, when compared with fenbufen, displayed a better overall fit to clofibric acid. Finally, interaction energies between the two drugs and the putative peroxisome proliferator-activated receptor ligand domain revealed that ibuprofen had a higher affinity for the receptor than fenbufen, but the difference was modest. It is concluded that ibuprofen, at doses far exceeding those employed clinically, is a weak inducer of both CYP4A1 activity and peroxisomal proliferation and these effects may be attributed to the presence of an aryl propionic acid moiety.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8179485&dopt=Abstract ibuprofen Motrin



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[Binding capacity of ibuprofen to muscle proteins]

[Article in German]

Menzel EJ, Kolarz G.

Institut fur Immunologie, Universitat Wien.

From former studies it is well known, that ibuprofen (CAS 15687-27-1) binds to muscular tissue in a higher degree than to tendons or ligaments. It is not known, however, what constituents of muscle tissue are responsible for this binding. Therefore the binding capacity of ibuprofen to different muscular proteins was studied. Actin, actomyosin, myosin, myoglobin, tropomyosin, lecithin, and native human collagen type I were incubated with 14C-ibuprofen and the specific binding was measured in relation to the total radioactivity. It could be shown that ibuprofen binds most markedly to actin. This binding could be inhibited by pre-incubation of ibuprofen with soluble actin. In comparison to the other proteins studied the specific binding of ibuprofen to actin was 4 to 5 times higher. As actin is a constituent of the cytoskeleton which plays an important role in generating oxygen radicals, its possible inhibition by ibuprofen could additionally explain the antiphlogistic effect of this compound.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8192699&dopt=Abstract ibuprofen Motrin



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NSAID use and efficacy in the emergency department: single doses of oral ibuprofen versus intramuscular ketorolac.

Wright JM, Price SD, Watson WA.

Department of Medicine, School of Medicine, University of Missouri-Kansas City.

OBJECTIVE: To compare the clinical efficacy of single doses of intramuscular ketorolac and oral ibuprofen in the emergency department (ED) treatment of acute pain. DESIGN: A retrospective analysis of data collected during a prospective survey of pain management efficacy. The design was noninterventional, and therapy was selected by the treating physician independent of the trial. SETTING: Urban teaching hospital adult patient emergency department. PARTICIPANTS: A convenience sample of ED patients in acute pain. INTERVENTIONS: Patients received ibuprofen 800 mg po (n = 95), or ketorolac 60 mg im (n = 30) as a single dose. Therapy was selected by the treating physician and was not influenced by the study. RESULTS: Data collected were a 100-mm visual analog pain scale at patient arrival and discharge, verbal description of pain relief, patient demographics, pain management data, and discharge diagnosis. Baseline pain intensity was higher in patients receiving ketorolac (77 mm median) than in those receiving ibuprofen (65 mm, p = 0.02). Pain relief was similar (p = 0.29) with either treatment when assessed by visual analog scale or patient definition of pain relief. CONCLUSIONS: A single dose of either nonsteroidal antiinflammatory drug produced similar pain relief in the general ED population during clinical treatment of pain. Ketorolac should not necessarily be considered a more effective analgesic than ibuprofen in these commonly used doses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8193414&dopt=Abstract ibuprofen Motrin



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The effect of colestipol and cholestyramine on the systemic clearance of intravenous ibuprofen in rabbits.

el-Sayed YM, al-Meshal MA, al-Angary AA, Lutfi KM, Gouda MW.

Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

The effect of oral administration of the non-absorbable anion-exchange resins cholestyramine and colestipol on the systemic clearance and other pharmacokinetic parameters of intravenously administered ibuprofen (25 mg kg-1) was studied in rabbits. Single doses of colestipol hydrochloride (0.4 g kg-1) or cholestyramine (0.17 g kg-1) were given 30 min before ibuprofen administration. In cholestyramine-treated rabbits a significant reduction in ibuprofen plasma concentration was observed compared with both control (water only) and colestipol-treated rabbits. Cholestyramine treatment resulted in a significant decrease in the terminal elimination half-life and the mean residence time. Furthermore, a 31% increase in the systemic clearance and 23% decrease in the area under the plasma concentration-time curve were also observed in cholestyramine-treated rabbits. Colestipol treatment did not change these parameters. The volume of distribution parameters (Vdss and Vd(area)) did not change following either treatment. The changes in the pharmacokinetic parameters are compatible with an acceleration of ibuprofen elimination induced by oral administration of cholestyramine and not by colestipol. This effect is thought to be due to augmentation of net biliary excretion through enteric binding.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8201531&dopt=Abstract ibuprofen Motrin



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In vitro and ex vivo cyclooxygenase inhibition by a hops extract.

Lemay M, Murray MA, Davies A, Roh-Schmidt H, Randolph RK.

Access Business Group LLC, California, USA.

While there has been much research on botanical materials as potential pain-relieving Cox inhibitors, it has not yet been demonstrated that oral consumption of botanical agents can inhibit Cox-2 activity in humans. In particular it would be of interest to determine whether any botanical anti-inflammatory has Cox-1-sparing activity, in order to reduce the risk of gastrointestinal side effects. This two-stage study was designed to first screen a variety of botanicals in vitro, and then to select one or more promising agents to test in human volunteers. Method: Seventeen botanical agents, putative anti-inflammatories or pain-relievers all, were evaluated in vitro for Cox-1 and -2 inhibitory potency and selectivity using a caco-2 cell line with ibuprofen as an active control. A promising compound, a hops extract high in alpha acids, showed a Cox-2/Cox-1 IC50 selectivity ratio of 0.06, compared to 4.2 for ibuprofen. Two different formulations of a standardized hops extract (resin and powder) were compared with ibuprofen in a double-blind, randomized, ex vivo study. Subjects consumed hops powder extract, hops resin extract, or ibuprofen, and provided blood samples before and at intervals for 9 h following the first dose. Plasma was extracted and analyzed in a validated Cox-1 and -2 inhibition assay. Results: There were no differences between active treatments or ibuprofen control in Cox-2 inhibitory action, as indicated by 9-hour Cox-2 Area over the Inhibition Curve (AOC); however, hops powder or hops resin extract produced a 9-hour Cox-1 / Cox-2 AOC ratio of about 0.4 (i.e., some degree of Cox-1 sparing), compared to 1.5 for ibuprofen (i.e. no Cox-1 sparing). Conclusion: Hops exhibited Cox-2 inhibition over 9 hours equivalent to ibuprofen 400 mg but had significant Cox-1 sparing activity relative to ibuprofen. Hops extracts may represent a safe alternative to ibuprofen for non-prescription anti-inflammation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15294636&dopt=Abstract ibuprofen Motrin



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Resolution of the enantiomers of ibuprofen; comparison study of diastereomeric method and chiral stationary phase method.

Ahn HY, Shiu GK, Trafton WF, Doyle TD.

Biopharmaceutic Research Branch, Food and Drug Administration, Washington, DC 20204.

In this study, an indirect diastereomeric method and a direct method utilizing a chiral stationary phase (CSP) were investigated for the resolution of ibuprofen enantiomers. In the indirect method, ethylchloroformate (ECF) and 2-ethoxy-1-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) were utilized as first-step derivatizing reagents in acetonitrile or toluene. In the direct CSP method, ibuprofen enantiomers were derivatized to p-nitrobenzyl ureides and then resolved on an (R)-(-)-(1-naphthyl)ethylurea CSP column. The derivatization procedure took place in 10 min with an overall inversion efficiency of 90.3%. Racemization was not observed under the derivatization conditions used. The HPLC-CSP method was utilized to study the pharmacokinetics of ibuprofen enantiomers in dog plasma after a single oral administration of 200 mg of ibuprofen racemate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8205243&dopt=Abstract ibuprofen Motrin



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Study of interaction of carprofen and its enantiomers with human serum albumin--II. Stereoselective site-to-site displacement of carprofen by ibuprofen.

Rahman MH, Maruyama T, Okada T, Imai T, Otagiri M.

Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.

The site-to-site displacement of carprofen, a site II-specific drug, bound to human serum albumin (HSA) by ibuprofen, another site II-specific drug, was qualitatively and quantitatively studied by circular dichroism (CD) and equilibrium dialysis (ED). Carprofen gives rise to different CD spectra at lower (1:1) and higher (3:1) molar ratios to HSA, indicating different mechanisms for the binding of this drug to its high and low affinity sites on HSA. Ibuprofen at a 5:1 molar ratio to HSA displaces carprofen at a molar ratio of 1:1 to HSA from its high affinity binding site (site II) to its low affinity site (site I), as shown by production of the CD spectrum similar to that obtained in the case of the carprofen-HSA complex at a molar ratio 3:1. As revealed by the ED experiments, the free fraction of carprofen at a molar ratio of 1:2 to HSA (2 x 10(-5) M) was not initially increased by the addition of ibuprofen at a lower concentration, but at a higher concentration (6 x 10(-5) M), the free fraction was increased by only 90%. When site I was sufficiently blocked by a site I-specific drug like warfarin or phenylbutazone (6 x 10(-5) M), there was about a 4-fold increase in the free fraction of carprofen caused by ibuprofen. This site-to-site displacement demonstrated by carprofen was found to be stereospecific as indicated by the highest interaction between the S(+)-enantiomers of carprofen and ibuprofen. Moreover, the displacement of carprofen occurred at the azapropazone region rather than the warfarin region of site I on HSA.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8250958&dopt=Abstract ibuprofen Motrin