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Stereoselective disposition of ibuprofen and flurbiprofen in rats.

Knihinicki RD, Day RO, Graham GG, Williams KM.

Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Darlinghurst, Australia.

(R)-2-Arylpropionates are often inverted to the pharmacologically active S-enantiomers in vivo, although there is significant interspecies variability in inversion. In order to provide a basis for determining the biochemical consequences of this unique process using rats as a model, it was important to establish the pharmacokinetic disposition of the enantiomers of ibuprofen, a drug well inverted in man and flurbiprofen, a drug apparently poorly inverted in man. Rats were dosed i.v. with a single dose of (R)- or (S)-ibuprofen (20 mg/kg), (R,S)-ibuprofen (40 mg/kg), (R)- or (S)-flurbiprofen (10 mg/kg), or (R,S)-flurbiprofen (20 mg/kg). Each treatment group consisted of six animals. Serial blood samples were withdrawn over a period of 6 h for ibuprofen and 10 h for flurbiprofen. These drugs were assayed in plasma by a stereospecific HPLC assay. The pharmacokinetics of the ibuprofen and flurbiprofen enantiomers were evaluated using a two-compartment open model with conversion of the R- to S-enantiomers in the central compartment. There was 50 +/- 4% inversion of (R)-ibuprofen, a figure similar to that observed in man and (R)-ibuprofen had a higher clearance (12.6 +/- 1.3 ml/min/kg) than (S)-ibuprofen (7.7 +/- 0.7 ml/min/kg; P less than 0.01). The clearance of (R)-flurbiprofen after racemate (2.3 +/- 0.1 ml/min/kg) was higher than its clearance when administered alone (1.7 +/- 0.2 ml/min/kg; P less than 0.01), indicating a pharmacokinetic interaction between the enantiomers (most probably at plasma protein binding sites). A corresponding difference was not observed for ibuprofen. There was a small amount of inversion of (R)-flurbiprofen as determined by area analysis (4.5 +/- 1.6%).(ABSTRACT TRUNCATED AT 250 WORDS)

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Production of S-(+)-ibuprofen from a nitrile compound by Acinetobacter sp. strain AK226.

Yamamoto K, Ueno Y, Otsubo K, Kawakami K, Komatsu K.

Pharmaceutical Research and Development Department, Asahi Chemical Industry Company Ltd., Miyazaki, Japan.

S-(+)-2-(4'-Isobutylphenyl)propionic acid [S-(+)-ibuprofen] was produced from racemic 2-(4'-isobutylphenyl)propionitrile (Ibu-CN) by an isolated bacterial strain, Acinetobacter sp. strain AK226. Ammonium acetate, acetonitrile, or n-butyronitrile as a carbon source in the culture medium was effective for bacterial growth and induction of this activity. The optimum pH of the reaction was around 8.0. S-(+)-Ibuprofen formed from Ibu-CN by resting cells was present in a 95% enantiomeric excess. Acinetobacter sp. strain AK226 appeared to possess a nitrilase for Ibu-CN because 2-(4'-isobutylphenyl)propionamide was not detected in the reaction mixture and 2-(4'-isobutylphenyl)propionamide was not hydrolyzed to S-(+)-ibuprofen. Since S-(+)-ibuprofen was preferentially produced while the R enantiomer of Ibu-CN was left almost intact over the time course of the reaction, the putative nitrilase appeared to be highly specific for the S enantiomer of Ibu-CN.

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Metabolic stereoisomeric inversion of 2-arylpropionic acids. On the mechanism of ibuprofen epimerization in rats.

Chen CS, Chen T, Shieh WR.

Department of Pharmacognosy and Environmental Health Sciences, College of Pharmacy, University of Rhode Island, Kingston 02881.

Kinetic and mechanistic studies are described for the metabolic stereoisomeric inversion of R-ibuprofen in rats. After oral administration of R-ibuprofen to rats, the plasma levels and enantiomeric compositions of ibuprofen and its major metabolite were monitored. Although individual animals exhibited great variations in metabolic rates, the concentration ratios of the S- and R-enantiomers of ibuprofen and also its metabolite remained roughly unchanged within 90 min. Even though it is generally believed that this bioconversion is strictly stereospecific in nature, chromatographic analysis revealed that S-ibuprofen also underwent metabolic inversion, however, at a much slower rate, than its R counterpart. The inversion mechanism was assessed by monitoring the loss of labeled deuterium from specifically deuterated ibuprofen. No significant isotope effect was observed for the metabolism of these deuterated derivatives. One deuterium atom was lost in the S-ibuprofen resulted from R-[2-2H]ibuprofen metabolism, whereas all the three deuterium atoms were retained when R-[3,3,3-2H3]ibuprofen was used as the substrate. These results reinforce the proposed mechanism that the inversion proceeds via a thioester carbanion intermediate. The pKa of the alpha-methine proton of ibuprofen N-acetylcysteamine thioester was shown to be 10.34 +/- 0.06, which excludes the possibility that ibuprofen may undergo inversion through the nonenzymatic isomerization of its acyl thioester.

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Ibuprofen, a putative anti-cataract drug, protects the lens against cyanate and galactose.

Roberts KA, Harding JJ.

Nuffield Laboratory of Ophthalmology, University of Oxford, U.K.

Cataract, the major cause of blindness world-wide, may be caused partly by modification of lens proteins by carbamylation and non-enzymic glycosylation (glycation) in some patients. Aspirin has been found to protect against these modifications and to prevent cyanate-induced opacification occurring in whole rate lenses. Ibuprofen is an aspirin-like anti-inflammatory drug which appeared as a protective factor against cataract in an Oxford case-control study. The binding of cyanate, galactose and glucose 6-phosphate to lens proteins, and the effect of ibuprofen on this reaction was investigated, as was cyanate-induced opacification in whole rat lenses. Labelled metabolite was incubated with bovine lens homogenate in the presence and absence of ibuprofen, and the incorporation of label into the lens homogenate was followed. Simultaneous and preincubation experiments were performed. Intact rat lenses were incubated in culture medium with and without cyanate and ibuprofen. The phase separation temperature was noted as the temperature at which opacity first appeared on cooling. Cyanate, galactose and glucose 6-phosphate bind progressively to lens proteins. Simultaneous incubation with ibuprofen reduces cyanate and galactose binding but not glucose 6-phosphate. Ibuprofen protects against opacities due to cyanate-induced phase separation. Ibuprofen has protected against cataract in the models of cataractogenesis in this study. It appears to have a different mechanism of action from that of aspirin. These studies provide some support for the idea, based on epidemiological findings, that ibuprofen might be a useful anti-cataract drug.

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Ibuprofen-associated renal impairment in a large general internal medicine practice.

Murray MD, Brater DC, Tierney WM, Hui SL, McDonald CJ.

Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana.

The authors determined the incidence of ibuprofen-associated renal impairment and risk factors for its development in 1908 patients treated with ibuprofen using data from a computerized medical records system. Renal impairment occurred in 343 patients (18%). Multivariable analysis revealed six independent predictors of renal impairment: age, prior renal insufficiency, coronary artery disease, male gender, elevated systolic blood pressure, and diuretic use. They then tested the degree to which ibuprofen contributed to the development of renal impairment by evaluating a control group of 3933 acetaminophen recipients. Neither ibuprofen nor acetaminophen was among the independent predictors of risk when all patients were considered (adjusted odds ratio, 1.05; 95% Cl, 0.88-1.26). However, two subsets of at risk patients had an ibuprofen effect: patients greater than or equal to 65 years of age who received ibuprofen were at greater risk of renal impairment as compared to acetaminophen recipients (adjusted odds ratio, 1.34; 95% Cl, 1.05 to 1.72) as were patients with coronary artery disease (adjusted odds ratio, 2.54; 95% Cl, 1.38 to 4.68). Their results suggest that elderly patients and patients with coronary artery disease are at risk for ibuprofen-associated renal impairment and therefore should have their renal function monitored when ibuprofen and possibly other nonsteroidal anti-inflammatory drugs are prescribed.

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Investigation of interference by nonsteroidal anti-inflammatory drugs in urine tests for abused drugs.

Rollins DE, Jennison TA, Jones G.

Center for Human Toxicology, University of Utah, Salt Lake City 84108.

Anecdotal and uncontrolled studies have suggested that nonsteroidal anti-inflammatory drugs produce false-positive results in immunoassay urine tests for some drugs of abuse. This study was performed in 60 volunteers who took ibuprofen as either a single 400-mg dose, or 200 mg three times a day, or 400 mg three times a day, and in 42 patients taking ibuprofen, naproxyn, or fenoprofen in therapeutic regimens for more than 30 days. Of the 510 urines collected from 102 individuals during these dosage regimens, two gave false-positive tests for cannabinoid by enzyme-mediated immunoassay (EMIA), one after 1200 mg of ibuprofen in three divided doses for one day and one in a patient taking naproxyn on a chronic basis; none was falsely positive for benzodiazepines. Two urines were false-positive for barbiturates by fluorescence polarization immunoassay (FPIA), one in a patient taking ibuprofen and one in a patient taking naproxyn. These data, collected prospectively, demonstrate the small likelihood of a false-positive immunoassay test result for cannabinoids, benzodiazepines, or barbiturates after the acute or chronic ingestion of ibuprofen, or after the chronic ingestion of naproxyn or fenoprofen.

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The effect of food on gastrointestinal (GI) transit of sustained-release ibuprofen tablets as evaluated by gamma scintigraphy.

Borin MT, Khare S, Beihn RM, Jay M.

Clinical Pharmacokinetics Unit, Upjohn Company, Kalamazoo, Michigan 49001.

The GI transit of radiolabeled sustained-release ibuprofen 800-mg tablets in eight healthy, fed volunteers was monitored using external gamma scintigraphy. Ibuprofen serum concentrations were determined from blood samples drawn over 36 hr following dosing. Sustained-release ibuprofen tablets containing 0.18% of 170Er2O3 (greater than 96% 170Er) in the bulk formulation were manufactured under pilot-scale conditions and were radiolabeled utilizing a neutron activation procedure which converted stable 170Er to radioactive 171Er (t1/2 = 7.5 hr). At the time of dosing, each tablet contained 50 mu Ci of 171Er. Dosage form position were reported at various time intervals. In five subjects the sustained-release tablet remained in the stomach and eroded slowly over 7-12 hr, resulting in gradual increases in small bowel radioactivity. In the remaining three subjects, the intact tablet was ejected from the stomach and a gastric residence time of approximately 4 hr was measured. This is in marked contrast to a previous study conducted in fasted volunteers in which gastric retention time ranged from 10 to 60 min. Differences in GI transit between fed and fasted volunteers had little effect on ibuprofen bioavailability. AUC and Tmax were unaltered and Cmax was increased by 24%, which is in agreement with results from a previous, crossover-design food effect study.

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Study of interaction between ibuprofen and nicotinamide using differential scanning calorimetry, spectroscopy, and microscopy and formulation of a fast-acting and possibly better ibuprofen suspension for osteoarthritis patients.

Oberoi LM, Alexander KS, Riga AT.

College of Pharmacy, Industrial Pharmacy Division, The University of Toledo, Toledo, Ohio 43606.

Solid-state interaction between ibuprofen and nicotinamide was studied using thermal, spectroscopic, and microscopic techniques. Solubility enhancement was calculated by high-performance liquid chromatography and suspension was found to be the suitable choice of formulation. Ibuprofen-nicotinamide binary mixtures were prepared by solvent evaporation method. Differential scanning calorimetry was used to investigate the stoichiometry and thermal properties of the complex between ibuprofen and nicotinamide. A sharp, single endotherm was observed between the melting endotherms of the individual components at a composition of 60% ibuprofen and 40% nicotinamide (w/w). Several spectroscopic techniques such as ultraviolet-visible, Fourier transform infrared, nuclear magnetic resonance, and powder X-ray diffraction were used to investigate the type of interaction between the two components. Optical microscopy was performed to observe changes with regard to particle size and crystal habit. It was concluded that the interaction that occurred was Pi donor-Pi acceptor in nature and too weak to sustain the integrity of the complex in the liquid state. The solubility of ibuprofen was enhanced by 62 times in the suspension when the concentration of nicotinamide was 13.3 mg/mL. The suspension prepared in this study has potential of being a better medication for pain relief in patients with osteoarthritis. (c) 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:93-101, 2005.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15526276&dopt=Abstract ibuprofen Motrin