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At least 19 recordsLinked to original sources
PubMed2002

Macromolecular prodrugs: X. Kinetics of fenoprofen release from PHEA-fenoprofen conjugate.

The kinetics of fenoprofen release from poly[alpha,beta-(N-2-hydroxyethyl-DL-aspartamide)]-fenoprofen conjugate (PHEA-Fen) in aqueous buffer solutions (pH 10 and 1.1), simulated gastric (SGF) and intestinal fluids (SIF) was studied. In borate buffer pH 10, the following rate constants were obtained: k=0.2659 (t=60 degrees C) and k=0.0177 h(-1) (t=37 degrees C) and in glycine buffer solution pH 1.1 k=0.0036 h(-1). In SGF and SIF fenoprofen release did not occur in significant extend within 12 h. The hydrolysis of the ester bond between the polymeric carrier and fenoprofen followed the pseudo first-order kinetics, with activation energy indicative for the breakage of a sigma bond (E(a)=100.6 kJ mol(-1)). The concentration of the released fenoprofen was determined by high performance liquid chromatography (HPLC).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1985

Stereoselective inversion of (R)-fenoprofen to (S)-fenoprofen in humans.

The concentrations of the (R)- and (S)-enantiomers of fenoprofen (alpha-methyl-3-phenoxy-benzeneacetic acid) were measured in plasma and urine of volunteers after oral administration of the (R,S)-racemate. In addition, urinary concentrations of the (R)- and (S)-4'-hydroxy metabolite of fenoprofen, the major metabolite, were measured. The (R)-enantiomer of fenoprofen was stereoselectively inverted to (S)-fenoprofen, which was the major isomeric form found in plasma and urine. A potency comparison of the enantiomers in vitro showed the (S)-isomer to be 35 times more active than the (R)-isomer in inhibiting the fatty acid cyclo-oxygenase pathway from human platelets. In vivo, the similar pharmacological potency of the two enantiomers previously observed in experimental animals may have been due to the rapid inversion of the (R)- to (S)-isomer.

Biotransformation↗
PubMedDate not supplied

A comparative analgesic study of propoxyphene, fenoprofen, the combination of propoxyphene and fenoprofen, aspirin, and placebo.

Groups of 27 inpatients with moderate or severe postoperative, fracture, or somatic pain were given single oral doses of propoxyphene napsylate (P), fenoprofen calcium (F), combinations of P and F, aspirin, or placebo. The increasing rank order for effectiveness, with doses in milligrams, was placebo, P50, aspirin 650, F600, F50, P50 + F50, F200, P50 + F600, P50 + F200, P200 + F50, P200, P200 + F200, and P200 + F600. The overall analgesic response to propoxyphene in this dose range (50 to 200 mg) increased linearly with increasing doses. The fenoprofen response also increased in proportion to the dose up to 200 mg; the overall response to 600 mg was not significantly different from that to 200 mg. Propoxyphene napsylate and fenoprofen calcium had additive analgesic effects. There were no drug-related adverse reports.

Aspirin↗
PubMed1977

Dose response to fenoprofen in an antipyretic study of fenoprofen and propoxyphene.

Single oral doses of 0, 50, 100, and 200 mg (acid equivalents) of fenoprofen calcium provide essentially linear increases in antipyretic activity over a six-hour period in patients with fever due to acute upper respiratory tract infection. During this same time interval, 200 and 400 mg doses apparently had equal efficacy. Single oral doses of 200 and 400 mg propoxyphene napsylate had no significant effect on the fever of patients with acute respiratory tract infections. No significant interaction between propoxyphene and fenoprofen, related to the antipyretic effect of fenoprofen, was demonstrated.

Administration, Oral↗
PubMed1987

Enantioselective disposition of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs. III. Fenoprofen disposition.

The disposition of fenoprofen enantiomers has been studied in nine healthy rabbits. A mean (S.E.M.) of 0.73 (0.07) of R-fenoprofen was inverted to S-fenoprofen and the distribution volumes for bound plus unbound R-fenoprofen and S-fenoprofen were 50.3 (4.5) and 98.5 (5.9) ml/kg, respectively. A model was developed which predicted the area under the S-fenoprofen plasma concentration-time curve after bolus administration of racemic fenoprofen. The mean (S.E.M.) predicted area, 2.1 (0.2) mg X min/ml/kg, was within 94% of the observed area 2.2 (0.2) mg X min/ml/kg. The effect of phenobarbital on the disposition of fenoprofen enantiomers was examined in an additional eight rabbits. During the control study the glucuronidation of R-fenoprofen exceeded the corresponding clearance term for the S-enantiomer by 2.1-fold. The clearances of individual enantiomers to their respective glucuronides increased after phenobarbital pretreatment by a mean 1.6-fold for R- and 2.3-fold for S-fenoprofen. The clearance of S-fenoprofen by processes other than glucuronidation and elimination of unchanged drug in urine was increased by a mean of 2.1-fold after phenobarbital pretreatment but the fractional inversion and the inversion clearance of R- to S-fenoprofen were not affected. These data indicate that on racemic fenoprofen administration the area under the curve for the pharmacologically active S-enantiomer would be reduced by phenobarbital pretreatment.

Animals↗
PubMed2002

Physical stability and solubility of the thermotropic mesophase of fenoprofen calcium as pure drug and in a tablet formulation.

The aim of this study was to investigate and compare the physical stability and solubility of the liquid crystalline form of fenoprofen calcium as pure drug and in a proprietary tablet formulation (Nalfon), and to investigate if a simple heat treatment of a proprietary tablet containing fenoprofen calcium may lead to a physically stable formulation with enhanced dissolution rate and apparent solubility. The liquid crystalline form of fenoprofen calcium (thermotropic mesophase) was prepared by heating the crystalline drug to 125 degrees C to remove the water of crystallisation. Differential scanning calorimetry investigation revealed an endothermic peak at 89 degrees C upon heating (liquid crystal formation) attributable to water loss from the crystalline dihydrate. The liquid crystalline order was maintained upon cooling. No interference of tablet excipients with the thermal behaviour of the drug in the tablet formulation was observed. The crystalline dihydrate and liquid crystalline forms of fenoprofen calcium could be differentiated by diffuse reflectance infra-red spectroscopy and X-ray powder diffraction, both as pure drug and in tablet formulation. The supercooled liquid crystal (thermotropic reversed hexagonal phase) alone and in preheated and ground tablets was physically stable when stored in a dry environment or at 33% relative humidities (RH) at both 20 and 40 degrees C for 2 months. At 40 degrees C and 75% RH the supercooled mesophase extensively converted to the crystalline dihydrate within 6 days. Liquid crystalline fenoprofen calcium stored at 20 degrees C and 75% RH showed only partial dihydrate conversion after 2 months of storage. The solubility of the crystalline dihydrate alone and from the tablet formulation was 2.8+/-0.2 mg/ml and 3.0+/-0.2 mg/ml (mean+/-s.d.), respectively, (not significantly different), whereas the maximum solubility of the liquid crystal was 5.0+/-0.3 mg/ml (mean+/-s.d.) and 6.9+/-0.6 mg/ml (mean+/-s.d.), respectively (significantly different). The difference in maximum solubility between the crystalline dihydrate form of fenoprofen calcium and the fenoprofen calcium mesophase was highly significant, for both the pure drugs and the tablet formulations. The dissolution rate of the liquid crystalline fenoprofen calcium in preheated, intact tablets was significantly lower than that of the crystalline form in non-preheated tablets. Gross visual changes and scanning electron microscopy indicated that the disintegration properties of the tablet may be detrimentally effected by heating the tablet to 125 degrees C, diminishing the beneficial effect of improved solubility of the liquid crystal. The study has shown that conversion of the crystalline form of fenoprofen calcium to the liquid crystal can enhance the apparent solubility of the pure drug and the drug in presence of tablet excipients, but that the conversion should be performed before tablet formulation in order to increase dissolution of this poorly water-soluble drug.

Chemistry, Pharmaceutical↗
PubMed1998

Peroxisome-proliferating effects of fenoprofen in mice.

We report on hepatic effects obtained in vivo by treating mice with different doses of fenoprofen, an arylpropionic acid previously shown to inhibit in vitro peroxisomal very long chain fatty acid oxidation. A strong and dose-related induction of peroxisomal palmitoyl-CoA oxidase, and of carnitine acyltransferase and acyl-CoA hydrolase activities was recorded in liver homogenates of mice fed diets supplemented with different contents [0.01, 0.05, 0.1, or 1% (w/w)] of fenoprofen for 6 d. Peroxisomal glycolate oxidase and mitochondrial butyryl-CoA, octanoyl-CoA, and palmitoyl-CoA dehydrogenases were unaffected or increased. Hepatic catalase activity was significantly increased in mice fed the diet with 0.05 and 0.1% fenoprofen but, surprisingly, was not stimulated in mice fed the 1% fenoprofen-containing diet. A time-related but unequal induction of acyl-CoA oxidases and catalase was observed with the 0.1% fenoprofen diet: at 21 d of treatment, the induction of lignoceroyl-CoA and palmitoyl-CoA oxidase activities were five-fold stronger than that of catalase activity. In mice treated with 1% fenoprofen for up to 6 d, only acyl-CoA oxidase activities were found to be significantly increased. Morphometric analysis of the liver peroxisomes in mice treated with 0.1% fenoprofen evidenced an increase in size, volume density, and surface density along with a reduced ratio between perimeter and area of the peroxisomal profiles. No morphological marker for very long chain fatty acid deposition could be detected in livers from fenoprofen-treated animals. Our findings clearly demonstrate that fenoprofen acts as a peroxisome proliferator in the liver of mice and do not support the occurrence of in vivo reduction of very long chain fatty acid oxidation in liver from treated animals.

Animals↗
PubMed1979

Linear pharmacokinetics of orally administered fenoprofen calcium.

The bioavailability of fenoprofen from three different fenoprofen calcium capsule formulations containing the equivalent of 60, 165, and 300 mg of fenoprofen was determined in two studies. In the first study, 12 subjects received one capsule of each formulation according to a three-period crossover design. The second study required each of 13 subjects to receive 300 mg of fenoprofen equivalent of the 60- and 300-mg capsules and 330 mg of the 165-mg capsule. The initial study provided information on the linearity of fenoprofen pharmacokinetics, and the second study established that the three capsule formulations were bioequivalent. The bioavailability parameters Cmax, tmax, and AUC0--12 hr for the drug in plasma were consistent with a linear pharmacokinetic model, as were the amounts of fenoprofen and hydroxyfenoprofen excreted in the urine. These data show linearity of kinetics for fenoprofen in plasma throughout the 60--300-mg dosage range after a single dose. Physical measurements of each capsule formulation drug content, weight variation, and dissolution showed the products to be uniform and readily soluble.

Adolescent↗
PubMed1993

Studies on the effect of fenoprofen on the activation and oxidation of long chain and very long chain fatty acids in hepatocytes and subcellular fractions from rat liver.

We studied the effect of fenoprofen on the activation of palmitic acid (C16:0), lignoceric acid (C24:0) and cerotic acid (C26:0) in microsomal and peroxisomal fractions from rat liver. Fenoprofen was found to inhibit the formation of palmitoyl-CoA in both microsomal and peroxisomal fractions whereas the formation of lignoceroyl-CoA and cerotoyl-CoA was not inhibited at all. In freshly isolated rat hepatocytes palmitic acid beta-oxidation was progressively inhibited at increasing concentrations of fenoprofen, most probably due to its inhibitory effect on palmitoyl-CoA synthetase activity. On the other hand, fenoprofen was also found to inhibit the beta-oxidation of lignoceric acid and cerotic acid in rat hepatocytes. It is shown that the acyl-CoA oxidase activity with lignoceroyl-CoA as substrate was inhibited by fenoprofen whereas the palmitoyl-CoA and pristanoyl-CoA oxidase activities were not inhibited by fenoprofen. This finding provides an explanation for the inhibitory effect of fenoprofen on lignocerate and cerotate beta-oxidation in hepatocytes.

Animals↗
PubMed1976

Fenoprofen therapy in large-joint osteoarthritis: double-blind comparison with aspirin and longterm experience.

This study, designed to evaluate fenoprofen in patients with osteoarthritis, consisted of two phases: I. A double-blind crossover comparison of fenoprofen, 200 to 600 mg every six hours, to aspirin, 325 to 975 mg every six hours; II. Longterm use of fenoprofen in an open study design. During the first part of the study, both fenoprofen and aspirin were significantly better than placebo in relieving the severity and duration of pain, and in reducing stiffness. In most of the variables fenoprofen was also slightly better than aspirin. The most frequently observed side effects were abdominal discomfort, headache, pruritus, nervousness, and tinnitus. Longterm administration demonstrated the safety of fenoprofen or periods exceeding two years. Fenoprofen did not precipitate or aggravate chronic disorders, nor did it mask the symptoms of any developing disease. No interaction with concomitant drug therapy was observed.

Aged↗
PubMed1995

Stereoselective reversible binding properties of the glucuronide conjugates of fenoprofen enantiomers to human serum albumin.

The stereoselective binding of fenoprofen enantiomers and fenoprofen glucuronide diastereomers to human serum albumin (HSA) was investigated using an ultrafiltration method. Fenoprofen glucuronides exhibit a considerable and stereoselective affinity to HSA, although less than seen for the parent drug. The (R)-glucuronide shows a higher affinity to HSA than the (S)-diastereomer. With the enantiomers, no significant difference could be detected. Diazepam and probenecid reduced the binding of the glucuronides, as well as that of the fenoprofen enantiomers. These results suggest that parent drug and its glucuronide metabolites occupy the same binding region on the albumin molecule. Both fenoprofen enantiomers, as well as racemic fenoprofen, are capable of reducing the extent of reversibly bound fenoprofen glucuronide.

Animals↗
PubMed1988

The stereospecific incorporation of fenoprofen into rat hepatocyte and adipocyte triacylglycerols.

The formation of triacylglycerols containing fenoprofen was studied in rat isolated adipocytes and hepatocytes incubated with [3H]glycerol and R or S fenoprofen. In both hepatocytes and adipocytes there was a high-affinity enzymatic process for the synthesis of triacylglycerol containing fenoprofen which was stereospecific for the R enantiomer. The apparent Km values for R fenoprofen were 1.0 microM in adipocytes and 2.8 microM in hepatocytes. These results are consistent with the proposed stereospecific formation of R-2-arylpropionyl-CoA thioesters resulting in the stereospecific formation of R-tri-acylglycerol at clinically relevant unbound fenoprofen concentrations. In isolated hepatocytes, but not adipocytes, a second low-affinity enzymatic process for the synthesis of triacylglycerol containing fenoprofen was also observed. However, this process (Km = 3780 microM) occurred at concentrations much higher than those found in man with usual doses.

Adipose Tissue↗
PubMed1995

Disposition of human drug preparations in the horse. IV. Orally administered fenoprofen.

Plasma and urinary concentrations of the non-steroidal anti-inflammatory drug fenoprofen were determined by a high-performance liquid chromatographic procedure following oral administration of a dose of 3 g to fed and fasted horses. In plasma, fenoprofen was present in detectable concentrations for 6-12 h. Free access to hay significantly reduced the peak plasma concentration and bioavailability of fenoprofen, and large interindividual differences in absorption and elimination pattern occurred. In fasted horses, fenoprofen was rapidly absorbed with a mean half-life of 0.10 h. Maximum concentrations were found 0.63 +/- 0.21 h after dosing. The elimination half-life was 0.9 h. As early as 1 h after dosage, fenoprofen could be detected in hydrolysed and unhydrolysed urine, and remained detectable up to 48 h. The maximum excretion rate and peak concentration occurred 2 h after administration, irrespective of the feeding schedule. In fed horses, a second maximum occurred after 9 h. The percentage of the dose excreted as unchanged fenoprofen in 12 h was 13.0 +/- 6.8%. A recovery of 21.9 +/- 7.4% and 42.2 +/- 7.0% of the dose was obtained after enzymatic and alkaline hydrolysis, respectively. At least three hydroxylated metabolites were detected in hydrolysed urine.

Administration, Oral↗
PubMed1990

Stereoselective analysis of fenoprofen and its metabolites.

Reversed-phase high-performance liquid chromatographic assays have been developed to quantitate simultaneously fenoprofen and its major metabolites as well as to distinguish between their R- and S- enantiomers following a single oral dose of 600 mg racemic fenoprofen to healthy volunteers. The compounds are extracted from plasma (after precipitation of plasma protein) or assayed directly in diluted urine samples employing a gradient solution on a C18 column and ultraviolet detection. Two internal standards, ketoprofen and flunoxaprofen, are used to allow measurement of very low (0.05 microgram/ml) and high (70 microgram/ml) concentrations in each sample. R- and S-fenoprofen glucuronides can be separated directly; the 4'-hydroxyfenoprofen conjugates are measured via an indirect method by comparing the concentration of 4'-hydroxyfenoprofen before and after hydrolysis. The R- and S-enantiomers of both parent and 4'-hydroxy metabolite are derivatized with L-leucinamide via an ethyl chloroformate intermediate and subsequently analyzed on a C18 column. Concentrations of metabolites found in plasma were low when compared to parent drug. The S/R ratio of fenoprofen in plasma always exceeds 1 and increases with time after dosage while the S/R ratio of its 4'-hydroxy metabolite remains almost unchanged at 1.1. R-Fenoprofen glucuronide disappears rapidly from plasma as compared to its S-antipode; a less pronounced difference is noted between R- and S-4'-hydroxyfenoprofen conjugates. Fenoprofen is almost completely excreted as its S-acyl glucuronides; the renal clearance of unchanged drug is very low.

Administration, Oral↗
PubMed1998

Interactions between fenoprofen sodium and poly (ethylene oxide).

Interactions of the amphiphilic drug fenoprofen sodium (FNa) in solution below and above its critical micelle concentration with poly (ethylene oxide) (PEO) of different chain length (PEO 400 to PEO 20000) and between a liquid crystalline formulation of fenoprofen (FLC; containing FNa, fenoprofen acid and water) and PEO were investigated, using surface tension measurements, viscometry, cloud point temperature measurements, [1H]NMR, polarised light microscopy, transmission electron microscopy, and differential scanning calorimetry. Interaction between FNa solutions and PEO: the investigations suggest that an interaction starts below the critical micelle concentration (CMC) of FNa. This can be concluded from [1H]NMR experiments (an upfield shift of the PEO proton signal was found at FNa concentrations below the CMC of FNa), surface tension measurements (absence of a critical association concentration) and cloud point temperature determinations. The surfactant does not seem to bind quantitatively on the PEO molecules (a higher FNa concentration was needed to cause the same upfield shift of the PEO proton signal than for more lipophilic surfactants, and no plateau phase in the surface tension reduction isotherm could be determined). Interactions were found to be independent from the chain length of the PEO. Interactions between FLC and PEO/pluronics: partial or complete dissolution of the fenoprofen mesophase (detected by [1H]NMR, polarised light microscopy and transmission electron microscopy) occurred after addition of PEO at concentrations between 2 and 10% (w/w), independent from the molecular weight of the PEO. A comparable amount of water added to the liquid crystalline samples does not change the mesophase into a liquid crystalline dispersion or a micellar solution. The liquid crystalline particles in the dispersion formed by the addition of PEO, had a higher transition temperature into an isotropic phase (between 54 degrees C and 57 degrees C), than in liquid crystalline dispersions without polymer (40 degrees C). The interactions between FNa and PEO can be interpreted in terms of a hydrophobic interaction with an association of the drug molecules on the polymer, i.e. the interaction between FNa and PEO occurs at a molecular rather than a micellar level. The interaction leads to a dissolution of the fenoprofen liquid crystal and the formation of an isotropic phase. No phase separation of the oily, amorphous, practically water insoluble fenoprofen acid could be found. Addition of PEO also seems to affect the composition of the remaining mesophase.

Anti-Inflammatory Agents, Non-Steroidal↗