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Mononuclear and binuclear copper(II) complexes of the antiinflammatory drug ibuprofen: synthesis, characterization, and catecholase-mimetic activity.

Abuhijleh AL.

Department of Chemistry, Birzeit University, West Bank, Via-Israel.

Two mononuclear copper(II) ibuprofenate adducts with imidazole or 2-methylimidazole and two binuclear copper(II) ibuprofenate adducts with metronidazole or caffeine have been prepared and characterized. Elemental analyses, UV-VIS, IR, EPR, and magnetic moment data for imidazole or 2-methylimidazole adducts are consistent with mononuclear square planar complexes that contain two ibuprofenato ligands and two N-containing imidazole ligands to give essentially a CuO2N2 chromophore. The above data for metronidazole or caffeine adducts are consistent with a binuclear structure as found for copper(II) acetate monohydrate and other copper(II) carboxylate dimers. In these complexes four carboxylate groups are bridging two copper(II) atoms, and two added bases coordinated at axial positions to form CuO4N chromophore around each copper. The catecholase-mimetic catalytic activities of the complexes have been determined by monitoring the formation of o-quinone from catechol. The catalytic activities of the mononuclear complexes are lower than those of the binuclear copper(II) ibuprofenate or its metronidazole or caffeine mono-adducts.

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Use of stable isotopes for evaluation of drug delivery systems: comparison of ibuprofen release in vivo and in vitro from two biphasic release formulations utilizing different rate-controlling polymers.

Theis DL, Lucisano LJ, Halstead GW.

Upjohn Company, Kalamazoo, Michigan 49001.

Certain delivery systems are intended to release the active ingredient in different phases to obtain the desired therapeutic effect. For these formulations, such as a bilayer tablet, it is desirable to distinguish and measure the release of drug from the different phases simultaneously. Mass spectrometric methods were developed to measure three ibuprofen isotopomers in serum and two in dissolution fluid. The analytical methods were linear (r > or = 0.992) over the concentration range of interest and recovery was greater than 99.2% for all isotopomers. Coadministration of [2H0]ibuprofen, [2H4]ibuprofen, and [2H7]ibuprofen to male beagles demonstrated that the isotopomers were bioequivalent and verified the absence of any kinetic isotope effect due to deuterium incorporation (p = 0.286). These methods were then used to evaluate a bilayer tablet formulation composed of an immediate release layer of 100 mg [2H4]ibuprofen and a sustained release layer with a drug load of 300 mg [2H0]ibuprofen. Two different rate-controlling polymer matrices that provided similar in vitro dissolution profiles were compared in the sustained release phase, while the immediate release formulation remained the same. In male beagles, the HPMC matrix delivered a significantly greater amount of ibuprofen (p < 0.05). The AUC was threefold greater for HPMC (1067 +/- 437 nmole*h/ml) versus EUDRAGIT (320 +/- 51), and Cmax was nearly four times greater (145 +/- 62.1 nmole/ml for HPMC versus 37.9 +/- 14.4 for EUDRAGIT).(ABSTRACT TRUNCATED AT 250 WORDS)

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Regional blood flow distribution in endotoxin-treated dogs: modification by ibuprofen.

Winslow C, Dorinsky PM.

Department of Medicine, Ohio State University, Columbus 43210.

PURPOSE: The aim of this study was to determine whether the improved hemodynamic profiles reported with cyclooxygenase inhibition during sepsis include improvements in tissue perfusion is unknown. Our hypothesis was that cyclooxygenase inhibition with ibuprofen will prevent the endotoxin-induced alterations in regional blood flow distribution from developing and/or restore the endotoxin-induced loss of responsiveness to intravascular volume expansion. METHODS: We measured cardiac output, regional blood flow, and total systemic shunt flow in dogs using radiolabeled 15-microns microspheres. These parameters were assessed in control (N = 10) and endotoxin-treated animals (N = 7). Additional endotoxin-treated animals (N = 7) were also pretreated with ibuprofen. RESULTS: Compared with controls, endotoxin-treated animals exhibited marked reductions in blood flow to most systemic organs that were not reversed with large, intravenous saline infusions (ie, isotonic saline; 40 mL/kg; N = 4). By contrast, although ibuprofen pretreatment (12.5 mg/kg; N = 7) completely prevented the reductions in mean arterial pressure caused by endotoxin from occurring, it did little to prevent the development of endotoxin-induced alterations in regional blood flow distribution. Nonetheless, in contrast to the endotoxin-treated animals, there were significant increases in cardiac output and blood flow to several organs after saline infusion in the ibuprofen-pretreated animals. CONCLUSIONS: Cyclooxygenase inhibition with ibuprofen has few direct effects on regional blood flow distribution after endotoxin. However, cyclooxygenase inhibition with ibuprofen does attenuate the endotoxin-induced decrease in vascular responsiveness to intravenous saline infusion.

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Tissue anti-adhesion potential of ibuprofen-loaded PLLA-PEG diblock copolymer films.

Lee JH, Go AK, Oh SH, Lee KE, Yuk SH.

Department of Polymer Science and Engineering, Hannam University, 133 Ojeong Dong, Daedeog Gu, Daejeon 306-791, Republic of Korea. jhlee hannam.ac.kr

This study was designed to evaluate the effect of polyethylene glycol (PEG) and nonsteroidal anti-inflammatory drug (ibuprofen) on the prevention of postsurgical tissue adhesion. For this, poly(L-lactic acid) (PLLA)-PEG diblock copolymers were synthesized by ring opening polymerization of L-lactide and methoxy polyethylene glycol (Mw 5000) of different compositions. The synthesized copolymers were characterized by gel permeation chromatography and 1H-nuclear magnetic resonance spectroscopy. PLLA-PEG copolymer films were prepared by solvent casting. The prepared copolymer films were more flexible and hydrophilic than the control PLLA film, as investigated by the measurements of glass transition temperature, water absorption content, and water contact angle. The drug release behavior from the ibuprofen (10 wt%)-loaded copolymer films was examined by high performance liquid chromatography. It was observed that the drug was released gradually up to about 40% of total loading amount after 20 days, depending on PEG composition; more drug release from the films with higher PEG compositions. In vitro cell adhesions on the copolymer films with/without drug were compared by the culture of NIH/3T3 mouse embryo fibroblasts on the surfaces. For in vivo evaluation of tissue anti-adhesion potential, the copolymer films with/without drug were implanted between the cecum and peritoneal wall defects of rats and their tissue adhesion extents were compared. It was observed that the ibuprofen-containing PLLA-PEG films with high PEG composition (particularly PLLA113-PEG113 film with PEG composition, 50 mol%) were very effective in preventing cell or tissue adhesion on the film surfaces, probably owing to the synergistic effects of highly mobile, hydrophilic PEG and anti-inflammatory drug, ibuprofen.

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Is the formation of R-ibuprofenyl-adenylate the first stereoselective step of chiral inversion?

Menzel S, Waibel R, Brune K, Geisslinger G.

Department of Experimental and Clinical Pharmacology, University of Erlangen-Nuernberg, Germany.

Coenzyme A thioester formation is reported to be the first step of chiral inversion of R-ibuprofen. In order to investigate the mechanism of this reaction adenylate derivatives of the ibuprofen enantiomers were synthesized chemically. R- and S-ibuprofenyl-adenylates as well as free acids were incubated with rat liver mitochondria in the presence of coenzyme A, MgCl2 with or without ATP. The optical antipodes formed by inversion and the coenzyme A thioester derivatives of both enantiomers were found after incubation of both R- or S-ibuprofenyl-adenylate and R-ibuprofen. By contrast, after incubation with S-ibuprofen neither R-enantiomer nor coenzyme A thioesters were detected. These experiments suggest that the formation of R-ibuprofenyl-adenylate may be the first stereoselective step of chiral inversion.

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Stereoselective disposition of ibuprofen in patients with renal dysfunction.

Chen CY, Chen CS.

Department of Family Medicine, College of Medicine, National Taiwan University, Taipei, Republic of China.

Ibuprofen-induced acute renal failure is thought to occur in clinical conditions where maintenance of renal function is prostaglandin-dependent. In this study we used a pharmacokinetic approach to assess the predisposing factors for this therapeutic pitfall. The pharmacokinetics of ibuprofen enantiomers was examined after a single dose of 800 mg of racemic ibuprofen in three groups of subjects: A) patients with pre-existing renal failure (n = 10); B) patients with underlying disease states other than renal failure (n = 11); and C) age-matched healthy controls (n = 10). Most of the patients with renal insufficiency showed elevated plasma (S)-ibuprofen levels, higher area under plasma concentration vs. time curve for (S)-ibuprofen and increased area under plasma concentration vs. time curves for (S)-/(R)-ibuprofen ratios as compared with their healthy counterparts. It appeared that the extent of metabolic activation of (R)-ibuprofen to the (S)-isomer in renally compromised patients was greater than that in a normal setting. Consequently, in susceptible patients, reduced renal clearance coupled with concomitant metabolic inversion leads to elevated (S)-ibuprofen levels which may exacerbate the ischemic effect as a result of the accentuated blockage of prostaglandin synthesis.

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Accelerated stability of Ibuprofen-Eudragit RSPM sustained release tablets, IR and DSC solid stability testing.

Abdel Rahman AA, Aboutaleb AE, Stamm A, Samy EM, Abdel-Rahman SI.

Faculty of Pharmacy, Assiut University, Assiut, Egypt.

Preformulated Ibuprofen-Eudragit RSPM sustained release tablets were subjected to accelerated stability testing at 25, 37 and 45 degrees C for 6 months. The stored tablets were evaluated for the intact drug in the formula, drug-polymer interaction and compatibility of the drug with the formulated excipients using infra red spectroscopy (IR) and differential scanning calorimetry (DSC). The IR spectrum of Ibuprofen in the tablets prepared by 15% w/v Eudragit RSPM as a granulating agent and containing 23% w/v Avicel pH 102 as an excipient is similar to the IR of standard Ibuprofen. There is no change in the IR spectra of the tablet components before and after storage of those tablets at the different investigated temperatures for 1, 3 and 6 months. The DSC thermograms of the Ibuprofen stored tablets show that the drug was still in the highly pure (> 98%) crystalline form and there was no significant degradation after storage indicating the stability of the drug on storage. In detecting Ibuprofen purity in the stored tablets, plotting of the sample temperature versus the reciprocal of the fraction of Ibuprofen melted showed deviation from Van 't Hoff linear plot.

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Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms.

Garcia-Martin E, Martinez C, Tabares B, Frias J, Agundez JA.

Department of Biochemistry and Molecular Biology and Genetics, School of Biological Sciences, University of Extremadura, Badajoz, Spain.

OBJECTIVE: Our objective was to identify genetic factors related to interindividual variability in the pharmacokinetics of ibuprofen and its enantiomers. METHODS: The time course for ibuprofen plasma concentration was measured by HPLC in 130 healthy individuals who received a single oral dose of 400 mg racemic ibuprofen. Genomic deoxyribonucleic acid was analyzed for common mutations at CYP2C8 and CYP2C9 genes that cause amino acid substitutions. RESULTS: Ibuprofen clearance values were 4.04 L/h (95% confidence interval [CI], 3.61-4.47 L/h), 2.79 L/h (95% CI, 2.07-3.52 L/h), and 0.40 L/h (95% CI, 0.37-0.43 L/h) for carriers of CYP2C8 genotypes *1/*1, *1/*3, and *3/*3, respectively, and 4.43 L/h (95% CI, 3.94-4.92 L/h), 3.26 L/h (95% CI, 2.53-3.99 L/h), 2.91 L/h (95% CI, 1.52-4.30 L/h), 2.05 L/h (95% CI, 0-6.37 L/h), 1.83 L/h (95% CI, 1.24-2.41 L/h), and 1.13 L/h (95% CI, 0.58-1.66 L/h) for carriers of the CYP2C9 genotypes *1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. The P values for comparison across nonmutated, heterozygous, and homozygous genotypes were as follows: P <.001 for CYP2C8*3, P <.005 for CYP2C9*2, and P <.001 for CYP2C9*3. The main genetic factor for reduced clearance of R-(-)-ibuprofen is the CYP2C8*3 allele, whereas the clearance for S-(+)-ibuprofen is influenced by CYP2C8*3 and CYP2C9*3 alleles to a similar extent. The CYP2C9*2 allele was associated with low clearance only when it was present in combination with the CYP2C8*3 allele. As compared with individuals with no mutations, individuals with the common genotype CYP2C8*1/*3 plus CYP2C9*1/*2 (19% of the population) displayed decreased ibuprofen clearance (mean, 65% [95% CI, 42%-89%]; P <.001). Individuals homozygous or double-heterozygous for CYP2C8*3 and CYP2C9*3 variant alleles (8% of the population) had extremely low ibuprofen clearance rates, with values ranging from 7% to 27% of the mean clearance rates among noncarriers of mutations (P <.001). No enantiospecific reduction of ibuprofen clearance was observed. CONCLUSION: Low ibuprofen clearance occurs in a substantial proportion of healthy subjects, is not enantiospecific, and is strongly linked to CYP2C8 and CYP2C9 polymorphisms.

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