Motrin
Methylated Nepsilon-dansyl-L-lysine as a fluorogenic reagent for the chiral separation of carboxylic acids.

Hayamizu T, Kudoh S, Nakamura H.

Takasaki-Laboratory of SmithKline Beecham Seiyaku, Gunma, Japan.

Dansyl amino acids having a free amino group and an asymmetric carbon atom were examined as a labeling reagent for chiral compounds containing carboxylic moieties to realize enantiomeric separation as well as fluorimetric determination. We tested dansyllysine by reacting it with (+)- and (-)-ibuprofen as a model carboxylic enantiomer. As the intramolecular carboxylic moiety of the dansyl amino acid interfered in the condensation reaction to form an amide bond with the carboxylic acid, the moiety was masked by methylation with trimethylsilyldiazomethane before the reaction. These derivatives were reacted with (+)- and (-)-ibuprofen and better enantiomeric resolution was achieved with methylated dansyllysine on a reversed-phase column. The derivatisation reaction was facilitated by the use of catalysts that are commonly employed in peptides synthesis. The reaction was completed within 5 min at room temperature when diethyl phosphorocyanidate was used. Due to the dansyl moiety, methylated dansyl-lysine enables a sensitive determination of ibuprofen with a fluorescence detector, in addition to the capability of enantiomer resolution. In tests, the detection limits for (+) and (-)-ibuprofen were 4 pmol per injection (S/N=3) at an excitation wavelength of 340 nm and an emission wavelength of 523 nm. Linear responses for the determination of (+) and (-)-ibuprofen in human urine were also demonstrated (r > or = 0.998) in the range from 10 to 1000 ng/ml. The precision and accuracy for urine samples spiked with (+)- and (-)-ibuprofen at 10, 100 and 1000 ng/ml were <10.1 and <14.6% (n=4), respectively.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9686889&dopt=Abstract ibuprofen Motrin



Motrin
Nabumetone in elderly patients with osteoarthritis: economic benefits versus ibuprofen alone or ibuprofen plus misoprostol.

Bentkover JD, Baker AM, Kaplan H.

Arthur D. Little, Inc., Cambridge, Massachusetts.

Nonsteroidal anti-inflammatory drugs (NSAIDs) vary in their potential to produce gastropathy. We compared the 3-month direct medical costs, including those associated with treating NSAID-induced adverse events, of nabumetone, ibuprofen, or ibuprofen plus misoprostol in 171 elderly patients with osteoarthritis. Total direct medical costs per patient treated were $US183 for nabumetone, $US252 for ibuprofen, and $US270 for ibuprofen plus misoprostol. Differences resulted from higher costs associated with treatment of drug-related adverse events with ibuprofen, and higher drug acquisition prices with the combination regimen. Sensitivity analyses demonstrated that direct costs with nabumetone approached those for the other 2 regimens if the price of nabumetone increased by 60%, the probability of lesion formation with nabumetone increased 4-fold, the probability of a lesion greater than 0.5cm being symptomatic and needing treatment was 31%, or the price of misoprostol decreased by 50%. Although this study found more lesions because of mandated endoscopies than might be recognised or treated in clinical practice, the results suggest an economic benefit of nabumetone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10160575&dopt=Abstract ibuprofen Motrin



Motrin
Ion-pairs of ibuprofen: increased membrane diffusion.

Sarveiya V, Templeton JF, Benson HA.

Faculty of Pharmacy, University of Manitoba, Manitoba, Canada.

The purpose of the present study was to determine the influence of pH and ion-pairing on the permeation of ibuprofen across polydimethylsiloxane (PDMS) membrane. The solubility of ibuprofen sodium was determined at a range of pH values. Saturated solutions were then used to determine the influence of pH on diffusion across PDMS as a model membrane. The apparent partition coefficient of ibuprofen sodium between n-octanol and phosphate buffer at various pH values was also investigated. Organic salts of ibuprofen using ethylamine, diethylamine, triethylamine and ethylene diamine as counter-ions were synthesized and the influence of these counter-ions on the permeation of ibuprofen was studied. The presence of ion-pairing was confirmed using 1H NMR and 13C NMR. Diffusion studies at different pH values (4.0, 5.0, 6.0, 7.0 and 8.0) indicated that ibuprofen sodium flux increased significantly with increasing pH from 4.0 to 7.0. Above pH 7.0 a decrease in diffusion was observed. The permeability coefficient increased with an increase in the amount of unionized acid. The apparent partition coefficient was directly related to the steady-state flux. The steady-state flux of ibuprofen increased up to 16-fold using different counter-ions. The highest flux was measured from ibuprofen triethylamine. The flux of ibuprofen salts across a lipophilic membrane can be increased by formation of ion-pairs. The extent of enhancement is associated with the lipophilicity, extent of ion-pairing and reduction in charge over the drug molecule. Copyright 2004 The Authors

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15231036&dopt=Abstract ibuprofen Motrin



Motrin
Effect of ibuprofen on thrombin-induced pulmonary edema in the rat.

Ahn CM, Sandler H, Wegener T, Saldeen T.

Department of Forensic Medicine, University of Uppsala, Sweden.

The effect of ibuprofen on thrombin-induced pulmonary edema was studied in rats. Thrombin infusion produced a significant increase in lung weight, wet weight/dry weight ratio and relative lung water content, a rise in mean pulmonary arterial pressure and a fall in mean systemic arterial pressure. It also caused a progressive decrease in PaO2 and a continuous increase in pH and PaCO2. Administration of either the S-isomer or R-isomer of ibuprofen at doses of 5 mg/kg body weight prior to thrombin infusion resulted in significant reduction in lung weight, wet weight/dry weight ratio and water content. The wet weight/dry weight ratio and the water content were somewhat lower after infusion of the S-isomer than of the R-isomer. Ibuprofen diminished the thrombin-induced increase in mean pulmonary arterial pressure and attenuated the early and late decrease in mean systemic arterial pressure caused by thrombin. Ibuprofen also stabilized thrombin-induced impairments in PaO2, PaCO2 and pH. The results thus indicate that ibuprofen effectively counteracts hemodynamic changes, stabilizes impairments in arterial blood gas variables and attenuates the increase in lung vascular permeability to protein with pulmonary edema caused by thrombin. The results also indicate a substantial R to S chiral inversion of ibuprofen in vivo in the rat.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7549227&dopt=Abstract ibuprofen Motrin



Motrin
Enantioselective effects of experimental diabetes mellitus on the metabolism of ibuprofen.

Oian X, Hall SD.

Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.

Diabetes mellitus is associated with numerous metabolic events that may influence the elimination of R- and S-ibuprofen and the inversion of R-ibuprofen. Short (3 days) and long (14 days) term experimental type I diabetes was induced in male Sprague-Dawley rats with streptozotocin, and genetically diabetic male Zucker rats were used as a model of type II diabetes. Isolated hepatocytes from long-term streptozotocin-treated rats exhibited significantly greater rate constants for ibuprofenyl-coenzyme A (CoA) formation (1.44 +/- 0.05 vs. 0.60 +/- 0.09 hr-1) and the elimination of R-ibuprofen (0.34 +/- 0.07 vs. 0.22 +/- 0.07 hr-1) relative to control (P < or = .05). These increases were consistent with significant induction of hepatic cytochrome P450 (1.14 +/- 0.45 vs. 0.54 +/- 0.10 nmol/mg protein) and an elevated hepatic free CoA content (313.4 +/- 48.5 vs. 172.9 +/- 38.6 nmol/g) relative to control (P < or = .05). In hepatocytes from type II diabetic rats there were significant reductions (P < or = .05) in the rate constants for ibuprofenyl-CoA formation (1.02 +/- 0.12 vs. 1.22 +/- 0.12 hr-1), R-ibuprofen elimination (0.21 +/- 0.06 vs. 0.34 +/- 0.10 hr-1) and S-ibuprofen elimination (0.41 +/- 0.07 vs. 0.73 +/- 0.11 hr-1) but no change in hepatic content of cytochrome P450 or CoA relative to control. The activity of ibuprofenyl-CoA synthetase in whole liver homogenate supplemented with ATP and CoA was not influenced by experimental diabetes. In both type I and type II diabetes there was a significantly greater exposure of hepatocytes to ibuprofenyl-CoA.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7562487&dopt=Abstract ibuprofen Motrin



Motrin
Disposition and reactivity of ibuprofen and ibufenac acyl glucuronides in vivo in the rhesus monkey and in vitro with human serum albumin.

Castillo M, Smith PC.

School of Pharmacy, University of North Carolina at Chapel Hill 27599-7360, USA.

The disposition of ibuprofen and ibufenac, an analog of ibuprofen with a history of severe adverse reactions, was investigated in Rhesus monkeys after oral administration. Plasma concentrations of the parent drugs and their glucuronides were measured by a direct HPLC method. Ibuprofen and ibufenac were rapidly absorbed and metabolized to their acyl glucuronides. The pharmacokinetic parameters of ibuprofen and ibufenac exhibited notable interanimal variability. Ibufenac tended to have a higher area under the plasma concentration vs. time curve (AUC), and its apparent clearance was lower. The plasma levels of acyl glucuronides were lower than parent drugs; the ratio of AUC in plasma for glucuronide/parent drug was 22.8% and 10.5% for ibuprofen and ibufenac, respectively. The degradation of ibufenac glucuronide in vitro was faster than ibuprofen glucuronide in aqueous buffer, human serum albumin, and human plasma solutions. Covalent binding of parent drug to protein via the acyl glucuronides was observed both in vitro and in vivo. The maximum protein adduct formed in vivo with ibufenac was 60% higher than found for ibuprofen, although exposure in plasma to its reactive acyl glucuronide, as measured by AUC, was lower. These data indicate that ibufenac glucuronide is a more reactive metabolite than ibuprofen glucuronide in vitro and in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7587932&dopt=Abstract ibuprofen Motrin



Motrin
Biodegradable ibuprofen-loaded PLGA microspheres for intraarticular administration. Effect of Labrafil addition on release in vitro.

Fernandez-Carballido A, Herrero-Vanrell R, Molina-Martinez IT, Pastoriza P.

Departamento de Farmacia y Tecnologia Farmaceutica, Facultad de Farmacia, Avda. Complutense s/n, Universidad Complutense, 28040 Madrid, Spain. afernand farm.ucm.es

The objective of this study was the development and optimisation of biodegradable PLGA microspheres loaded with ibuprofen destined for intraarticular administration. The formulation was designed to provide "in vitro" therapeutic concentrations of ibuprofen (8 microg/ml) for as long as possible. The solvent evaporation method based on an o/w emulsion was used to form the microparticles. The polymer used was Poly (D,L-lactide-co-glicolide) 50:50 (PLGA), of different molecular weights (Mw) (34,000, 48,000 and 80,000 Da). In order to get a more controlled release rate of ibuprofen, a biodegradable oil, Labrafil M1944CS, polyethylene glycol 300 derivative, was used as an additive. The formulation was optimised by means of an experimental design, 2(3) being the variables: X(1) = PLGA Mw; X(2) = initial ibuprofen:polymer ratio; X(3) = percentage of Labrafil. The theoretical profile yielding in vitro "therapeutic" concentrations of ibuprofen (8 microg/ml) was calculated. The experimental profiles obtained for the formulations tested were compared with the theoretical one by means of the difference factor (f(1)). In all cases, the addition of Labrafil lowered the initial ibuprofen burst, prolonging the release rate of the drug from 24 h (without additive) up to 8 days incorporating the oil. The microspheres made from the PLGA (Mw = 34,000 Da) with Labrafil addition (10%) and ibuprofen:polymer (15%) ratio (formulation 1) yielded the most suitable release profiles. Forty milligram of the selected formulation (formulation 1), was sufficient to provide in vitro "therapeutic" concentrations of ibuprofen (8 microg/ml) up to 8 days. Labrafil modulates the release rate of donor-acceptor substances such as ibuprofen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15234792&dopt=Abstract ibuprofen Motrin



Motrin
Influence of age on the stereoselective disposition and metabolism of ibuprofen in humans.

Chen CY.

Department of Family Medicine College of Medicine National Taiwan University, Taipei, R.O.C.

Ibuprofen is widely used in the treatment of pain and inflammatory disorders. Metabolic events that occur within the pharmacokinetic behavior of ibuprofen enantiomers create problems for patients, particularly the elderly and those with conditions where the maintenance of renal function is prostaglandin-dependent. Eighteen healthy volunteers of two different age groups received an oral dose of 800 mg of racemic ibuprofen, and the pharmacokinetic profiles of (R)- and (S)-ibuprofen metabolism were examined. The results showed reduced ibuprofen clearance in the older group, as indicated by elevated values of T1/2 (R), AUC(R) and AUC(S), as well as reduced clearance/fraction of absorption (R). Clearly, age is a risk factor for ibuprofen-related renal failure. The aging process, functional changes in drug metabolism and disposition contribute to the increased incidence of ibuprofen-related toxicity in the elderly.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7613251&dopt=Abstract ibuprofen Motrin