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Intracellular distribution of ibuprofen within monocytes.

Menzel EJ, Binder M, Kolarz G.

Institute of Immunology, University of Vienna, Austria.

The interaction of ibuprofen (CAS 15687-27-1) with muscle proteins was investigated in vitro and binding to actin was found to be more marked than to other muscle proteins. Actin polymerization, however, was not influenced by this interaction. The kinetics of ibuprofen internalization by human monocytes/macrophages from peripheral blood at 37 degrees C and its partitioning to different cellular compartments was studied and compared to the actin content of these subcellular fractions. The bulk of cell-bound ibuprofen (89.7%) was found in the cell debris fraction (1,000 g sediment), 7.3% were recovered in the 10,000 g sediment, only 0.5% in the 100,000 g sediment and 2.5% in the cytosolic fraction. The distribution of F-actin to the different subcellular fractions was verified by fluorescence analysis using NBD-phallacidin. Four times more F-actin was found in the 1,000 g sediment than in the 10,000 g fraction, while the microsomal fraction contained only 8% of total F-actin. In the cytosol, significant amounts of soluble actin were detected. These data indicate that ibuprofen could theoretically interact with actin in all the cellular subfractions to which it is distributed after internalization.

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Inhibition of prostaglandin synthesis in newborn pigs increases cerebral microvessel prostaglandin F2 alpha and prostaglandin E2 receptors, their second messengers and vasoconstrictor response to adult levels.

Li DY, Abran D, Peri KG, Varma DR, Chemtob S.

Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.

We recently reported that the density of prostaglandin (PG) F2 alpha and E2 receptors (FP and EP) on the cerebral microvasculature of the newborn is less than on that of the adult animal. This study tests the hypothesis that higher levels of PGF2 alpha and PGE2 in the newborn than in the adult brain might down-regulate FP and EP and their functions in the cerebral microvasculature. Newborn pigs (1-2 days old) were treated with ibuprofen (40 mg/kg i.v.) every 6 h for 48 h; and cerebrovascular FP and EP density, receptor-coupled second messenger production and cerebral vasoconstrictor responses to PGF2 alpha and PGE2 were determined. The results showed that ibuprofen treatment in the newborn increased brain microvascular FP and EP densities to levels found in the brains of adult pigs. This up-regulation of prostaglandin receptors was also observed in isolated newborn brain microvessels incubated for 48 h with ibuprofen. PGF 2 alpha, fenprostalene (PGF2 alpha analog), PGE2, 17-phenyl trinor PGE2 (EP1 receptor subtype agonist) and M&B 28,767 (EP3 agonist) caused a significantly greater increase in inositol 1,4,5-triphosphate production in brain microvessels of ibuprofen-treated than in brain microvessels of saline-treated newborn pigs. The cerebral vasoconstrictor effects of PGF2 alpha, 17-phenyl trinor PGE2 and M&B 28,767 were also significantly increased in newborn pigs treated with ibuprofen to levels comparable to those of adults. However, the steady-state level of FP mRNA in cerebral microvasculature did not differ between saline-treated newborn, ibuprofen-treated newborn and adult pigs. It is concluded that the low FP and EP densities in newborn brain microvessels are a result of high levels of brain prostaglandins and that these receptors, receptor-coupled second messengers and cerebral vasoconstrictor responses to FP, EP1 and EP3 stimulation can be up-regulated to adult levels by decreasing endogenous prostaglandin production. The changes in receptor levels were not related to steady-state levels of receptor mRNA in brain microvessels.

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Assessment of gentamicin-induced nephrotoxicity in rats treated with low doses of ibuprofen and diclofenac sodium.

Farag MM, Mikhail M, Shehata R, Abdel-Meguid E, Abdel-Tawab S.

Medical Research Institute, Alexandria University, Egypt.

1. The effects of two non-steroidal anti-inflammatory drugs, ibuprofen (20 mg day-1 kg-1) and diclofenac sodium (2.5 mg day-1 kg-1), on the severity of gentamicin-induced nephrotoxicity were evaluated in rats. 2. Administration of gentamicin (100 mg day-1 kg-1) for 5 days resulted in a significant increase in renal cortical total phospholipids accompanied by a significant decrease in cortical Na+, K(+)-ATPase activity. These changes were associated with a significant decrease in body weight and increases in kidney weight, serum creatinine and urea nitrogen. 3. In rats treated simultaneously with both gentamicin and either ibuprofen or diclofenac sodium for 5 days, all the measured parameters of renal dysfunction were similar in magnitude to those observed in rats treated with gentamicin alone. 4. In contrast, rats treated with either ibuprofen or diclofenac sodium for 27 days and injected concurrently with gentamicin during the last 5 days of the treatment period had significantly higher kidney weight, lower renal cortical Na+, K(+)-ATPase activity and higher cortical phospholipid content, serum creatinine and urea nitrogen than did rats treated with gentamicin alone. A 27-day treatment with ibuprofen or diclofenac sodium alone resulted in no change in renal function. 5. These results demonstrate that gentamicin nephrotoxicity was potentiated after the long (27 days) but not after the short (5 days) period of treatment with ibuprofen and diclofenac sodium. Thus, prolonged administration of non-steroidal anti-inflammatory drugs should be considered as a risk factor that may increase the nephrotoxic potential of gentamicin.

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Bioavailability and pharmacokinetics of ibuprofen in the broiler chicken.

Roder JD, Chen CL, Chen H, Sangiah S.

Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater 74078, USA.

The intravenous, intramuscular and oral pharmacokinetics of ibuprofen in broiler chickens were investigated. In a preliminary study, plasma ibuprofen concentration-time profiles, following i.v. (25 mg/kg) dosing were best described by a 2-compartment model. After intravenous administration, the volume of distribution at steady-state (Vd(ss)), the total systemic clearance (ClB), the elimination half-life (t1/2 beta) and the MRT were 0.303 L/kg, 482.3 ml/h.kg, 2.71 h and 1.02 h, respectively. After intramuscular administration of ibuprofen, the tmax and Cmax were 0.37 h, and 42.2 micrograms/mL, respectively, with an estimated bioavailability of 46.7%. After oral administration of ibuprofen, the tmax and Cmax were 0.31 h and 23.91 micrograms/mL, respectively, with an estimated bioavailability of 24.2%. This is a preliminary study, examining the use of ibuprofen in broiler chickens, and should be followed by tissue residue and efficacy studies in different disease states.

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Clofibric acid increases the undirectional chiral inversion of ibuprofen in rat liver preparations.

Roy-de Vos M, Mayer JM, Etter JC, Testa B.

Institut de chimie therapeutique, Universite de Lausanne, BEP, Switzerland.

1. The formation of (S)-ibuprofen from (R)-ibuprofen was monitored in perfused rat livers and in rat hepatocytes and the rate constants calculated. 2. Pre-treatment of animals for three days with clofibric acid markedly increased the (R)-to-(S) inversion of ibuprofen in both preparations. In contrast, clofibric acid did not elicit such a reaction with flurbiprofen, an analogue that does not undergo inversion under control conditions. 3. An increase in the chiral inversion was also seen when clofibric acid was added to the perfusion medium or to hepatocyte suspensions. In the latter system this increase was shown to be concentration dependent. 4. Pre-treatment of rat combined with addition of clofibric acid to the perfusion medium produced a cumulative stimulation of (R)-to-(S) inversion of ibuprofen. 5. Clofibric acid added to hepatocyte suspensions transiently increased intracellular concentrations of coenzyme A whereas (R)-ibuprofen transiently decreased CoA concentrations. The two effects cancelled each other upon co-incubation of the two compounds. 6. It is postulated that the metabolic interaction observed between clofibric acid and (R)-ibuprofen may be due to changes in intracellular concentrations of CoA.

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Isolation and characterization of rat liver microsomal R-ibuprofenoyl-CoA synthetase.

Brugger R, Garcia Alia B, Reichel C, Waibel R, Menzel S, Brune K, Geisslinger G.

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

Microsomal long-chain acyl-CoA synthetase (EC 6.1.2.3.) has been suggested to be involved in the stereoselective formation of the CoA thioester of ibuprofen. In this study, we demonstrated that the microsomal enzyme from rat liver responsible for palmitoyl-CoA synthesis also catalyzes the formation of R-ibuprofenoyl-CoA in a Mg(2+)- and ATP-dependent process. Long-chain acyl-CoA synthetase from rat liver microsomes was purified to homogeneity as evidenced by SDS-gel electrophoresis. Simultaneous measurements of palmitoyl-CoA and R-ibuprofenoyl-CoA formation with HPLC in various fractions and purification steps during protein isolation revealed a high correlation between both activities. The purification procedure included solubilization of the microsomes obtained from rat livers with Triton X-100 and subsequent chromatography of the 100,000 x g supernatant on blue-sepharose, hydroxyapatite, and phosphocellulose. The purified enzyme exhibited an apparent molecular weight of 72 kDa as estimated by SDS gel electrophoresis, with specific activities of 71 nmol.min-1.mg-1 protein and 901 nmol.min-1.mg-1 protein for formation of R-ibuprofenoyl-CoA and palmitoyl-CoA, respectively. Palmitoyl-CoA formation catalyzed by the purified enzyme exhibited biphasic kinetics indicative of two isoforms, a high-affinity (KM 0.13 +/- 0.11 microM), low-capacity form and a low-affinity (KM 81 +/- 11.5 microM), high-capacity form. In contrast, measurement of R-ibuprofenoyl-CoA synthesis over a concentration range from 5 to 3000 microM showed the participation of a single CoA ligase with a KM of 184 +/- 19 microM, corresponding to the low-affinity isoform of palmitoyl-CoA synthesis with a marked enantioselectivity towards the R-form of ibuprofen. R-ibuprofenoyl-CoA formation of the enzyme preparation was inhibited by palmitic acid (KI 13.5 +/- 0.5 microM) and S-ibuprofen (KI 405 +/- 10 microM). In summary, these data give strong evidence for the identity of R-ibuprofenoyl-CoA and long-chain acyl-CoA synthetase.

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Acute gastrointestinal toxic effects of suspensions of unencapsulated and encapsulated ibuprofen in rats.

Adeyeye CM, Bricker JD, Vilivalam VD, Smith WI.

Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.

PURPOSE. The study examined the gastrointestinal (GIT) toxicity effects of suspensions of encapsulated and unencapsulated ibuprofen in male Wistar rats. METHODS. Rats were randomly divided into four experimental groups and four control groups, and dosed with suspensions of encapsulated and unencapsulated ibuprofen (17 mg/kg and 44 mg/kg). Bethanechol chloride, a cholinomimetic agent (5 mg/kg), was administered 30 minutes after the dosing, to induce gastric irritation. Blood plasma concentrations were monitored in another set of rats for 12 hours using the encapsulated and unencapsulated systems, to establish drug release and exposure to the mucosa. RESULTS. Evaluation of the upper GI segments after 7 hours revealed that the 44 mg/kg dose of the encapsulated drug significantly reduced the number of lesions present compared to the unencapsulated drug (p < 0.05). At 17 mg/kg, the encapsulated drug reduced toxicity, but not significantly compared to the unencapsulated ibuprofen. Necrosis of the mucosa was observed histopathologically in the unencapsulated drug at both doses, whereas the encapsulated drug treatment revealed preserved mucosa. The encapsulated system had a maximum plasma concentration, Cmax, and time taken to reach Cmax, (Tmax) of 26.7 mu g/ml +/- 1.5 and 3.6 +/- 0.2 hr, respectively. The area under the plasma concentration-time curve, (AUC(0-12)), was 158.8 +/- 23.5 mu g.h/ml, confirming drug release and absorption. CONCLUSIONS. Encapsulation of ibuprofen significantly reduced gastrointestinal toxicity especially at the higher dose level and drug was released enough to subject the GI mucosa to irritation, but without the usual toxic effects.

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Transfer of different nonsteroidal antiinflammatory drugs via the lymphatic system in the rat.

Oelkers R, Ionac M, Erb K, Brune K, Geisslinger G.

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

The motility of lymphatic vessels is regulated by arachidonate metabolites and can, therefore, be altered by cyclooxygenase blockers such as nonsteroidal antiinflammatory drugs (NSAIDs). To investigate the transfer of different NSAIDs via the lymphatic system, pharmacokinetics in plasma and lymph after peroral administration of three model compounds (namely, racemic ibuprofen, tenoxicam, and nabumetone) were investigated in rats. Microsurgical cannulation of the thoracic duct allowed cumulative sampling of lymph fluid up to 48 hr (N = 16). Pharmacokinetic parameters in plasma were determined in a control group (N = 12). Concentrations of R-ibuprofen, S-ibuprofen, tenoxicam, nabumetone, and the metabolites OH-ibuprofen, COOH-ibuprofen and 6-methoxy-2-naphthylacetic acid (6MNA; a metabolite of nabumetone) were monitored in lymph and plasma by HPLC. The observed peak concentrations in lymph of the investigated drugs are likely to produce different biological effects with regard to cyclooxygenase-1 inhibition. To quantify the appearance in lymph fluid, a "lymphatic clearance" of the investigated compounds was defined by dividing the amount recovered in lymph by the corresponding area under the plasma concentration-time curve. The "lymphatic clearance" differed substantially between the investigated compounds (mean +/- SD: R-ibuprofen, 19.8 +/- 9.4; S-ibuprofen, 9.6 +/- 3.6; tenoxicam, 32.5 +/- 31.3; nabumetone, 133.6 +/- 75.2; 6MNA, 18.3 +/- 8.5 microliters/min/kg). Overall recovery of the investigated compounds in lymph did not exceed 5% of the doses given. The known fact that lymphatic drainage is regulated by arachidonate metabolites suggests that NSAIDs differing in their transfer via the lymphatic system could result in different responses of lymphatic vessels to an inflammatory fluid load.

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