Arch Int Pharmacodyn Ther. 1984 Mar;268(1):4-11.
Effects of indomethacin and naproxen on renal p-amino-hippurate (PAH) excretion in rats during postnatal development.

Hably C, Banki K, Bartha J, Braunlich H.

Effects of the cyclooxygenase inhibitors indomethacin and naproxen on renal PAH excretion were studied in volume-expanded and sodium-loaded, conscious rats of different ages. Indomethacin and naproxen reduce renal PAH excretion in 5- and 10-day-old rats but not in rats of older ages. Findings can be explained by a decrease in glomerular filtration rate. In addition, a competitive inhibition of PAH transport by the organic acids indomethacin and naproxen must be mentioned. Until now it is not known whether or not there is a direct or indirect influence of prostaglandins on processes involved in tubular PAH transport.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6428338&dopt=Abstract Naproxen Naprosyn





Drug Metab Dispos. 1996 Jan;24(1):126-36.
[O-methyl 14C]naproxen O-demethylase activity in human liver microsomes: evidence for the involvement of cytochrome P4501A2 and P4502C9/10.

Rodrigues AD, Kukulka MJ, Roberts EM, Ouellet D, Rodgers TR.

Drug Metabolism Department, Abbott Laboratories, Abbott Park, IL 60064, USA.

Cytochrome P450 (CYP) activity in human liver microsomes was measured after the O-demethylation of [O-methyl 14C]naproxen (NAPase). The formation of [14C]formaldehyde in the presence of microsomes was described by an apparent KM(1) and Vmax(1) of 0.16 +/- 0.09 mM and 4.1 +/- 2.8 nmol HCHO/min/mg protein (mean +/- SD; N = 5 different livers), respectively, over a relatively wide naproxen concentration (5-1600 microM) range. With two sets of microsomes, a high KM NAPase component was also detected (mean KM2 = 2.7 mM; mean Vmax2 = 23 nmol HCHO/min/mg). As expected, the O-demethylation of naproxen (0.4 mM) was found to be highly correlated with tolbutamide hydroxylase (TOLase) activity in a panel of human liver microsomes (r = 0.82, p < 0.01, N = 10) and was inhibited (32-54%) by a number of purported CYP2C (CYP2C9/10) inhibitors/substrates (e.g. phenytoin, sulfaphenazole, tienilic acid, tolbutamide, and ibuprofen). Only marginal decreases in activity (< or = 14%) were observed with inhibitors of other CYP proteins. However, NAPase activity was also found to correlate significantly with CYP1A2 [ethoxyresorufin O-deethylase (ERODase)] activity (r = 0.68, p < 0.05, n = 11). In addition, the reaction was inhibited (36-75%, N = 11 different livers) by furafylline (FURA), a CYP1A2-selective mechanism-based inhibitor. The effect of FURA and tienilic acid was additive, leading to 90 +/- 4.2% inhibition of NAPase activity. FURA-inhibited activity also significantly correlated with ERODase activity (r = 0.78, p < 0.01, N = 11), whereas tienilic acid-inhibited activity correlated with TOLase activity (r = 0.63, p < 0.05, N = 10). In human B-lymphoblast microsomes, cDNA-expressed CYP1A2 exhibited relatively high activity (KM = 0.25 mM; Vmax = 24 nmol/min/nmol CYP), when compared with CYP2A6, CYP2D6, CYP2E1, CYP2B6, and CYP3A4. The kinetic parameters for reconstituted purified human liver microsomal CYP2C9 (KM = 0.43 mM; Vmax = 11 nmol/min/nmol CYP) were comparable with those of CYP1A2. It is concluded that the O-demethylation of naproxen (< or = 0.4 mM) is catalyzed by CYP2C subfamily members (CYP2C9/10) and CYP1A2 in human liver microsomes.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8825200&dopt=Abstract Naproxen Naprosyn





Arzneimittelforschung. 1975 Feb;25(2A):278-81.
Chemistry and pharmacology of naproxen.

Dorfman RI.

The need for a nonsteroidal anti-inflammatory agent effective in rheumatoid arthritis, osteoarthritis, gout, ankylosing spondylitis and related diseases with reduced side effects when compared to existing drugs led us to develop naproxen: d-2-(6'-methoxy-2'-naphthyl)-propionic acid. This new agent is a highly effective anti-inflammatory, analgetic, and antipyretic agent in the rodent administered orally. In a rat paw edema test for anti-inflammatory activity naproxen was 55 times more active than aspirin. Analgetic activity was assessed by three different assay procedures. In the mouse phenylquinone writhing test naproxen was 7 times as effective as aspirin. In the rat yeast-induced paw edema and the rat carrageenin paw edema analgetic assays the test compound was 10 and 20 times more effective than aspirin, respectively. A yeast-induced pyresis model in the rat indicated that naproxen was 22 times more potent than the standard aspirin. The relative potency of naproxen to phenylbutazone and indometacin is presented.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1173774&dopt=Abstract Naproxen Naprosyn





J Chromatogr. 1992 Jun 10;577(2):362-5.
Simultaneous determination of (R)- and (S)-naproxen and (R)- and (S)-6-O-desmethylnaproxen by high-performance liquid chromatography on a Chiral-AGP column.

Andersen JV, Hansen SH.

PharmaBiotec Research Center, Royal Danish School of Pharmacy, Department of Organic Chemistry, Copenhagen.

A high-performance liquid chromatographic method for the simultaneous determination of both enantiomers of naproxen and its metabolite 6-O-desmethylnaproxen has been developed. The separation is performed on a column containing alpha 1-acid glycoprotein as the chiral selector. The method has been used for the determination of the enantiomeric purity of the drug substance and the metabolite, and for the simultaneous determination of all four compounds in biological fluids.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1400768&dopt=Abstract Naproxen Naprosyn





Jpn J Pharmacol. 1984 Sep;36(1):77-85.
Pharmacological properties of a new anti-inflammatory compound, alpha-(3,5-di-tert-butyl-4-hydroxybenzylidene)-gamma-butyrolacto ne (KME-4), and its inhibitory effects on prostaglandin synthetase and 5-lipoxygenase.

Hidaka T, Hosoe K, Ariki Y, Takeo K, Yamashita T, Katsumi I, Kondo H, Yamashita K, Watanabe K.

The pharmacological effects of a new anti-inflammatory compound, alpha-(3,5-di-tert-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), and its inhibitory effects on arachidonate prostaglandin synthetase and 5-lipoxygenase activities were examined. KME-4 showed anti-inflammatory activity. It was less active than indomethacin, but more active than naproxen and ibuprofen in carrageenin-induced paw edema in rats; and it was less active than indomethacin, equipotent as naproxen, but more active than ibuprofen in granuloma formation in rats. The ulcerogenic activity of KME-4 was weaker than indomethacin and naproxen, but stronger than ibuprofen in starved rats. The ratio of UD50 stomach to ED30 carrageenin edema or to ED25 granuloma for KME-4 showed higher values than those of the reference drugs. KME-4 showed antipyretic activity in yeast-induced fever in rats. It also inhibited platelet aggregation induced by arachidonic acid and protected rabbits from arachidonic acid-induced death. Furthermore, KME-4 was found to be equipotent in inhibiting both prostaglandin synthetase and 5-lipoxygenase activities of rat basophilic leukemia cells, unlike indomethacin, naproxen and ibuprofen. It also inhibited the prostaglandin synthetase activity of bovine seminal vesicle. The present findings indicate that KME-4 may be a new type of anti-inflammatory drug with dual prostaglandin synthetase and 5-lipoxygenase inhibition.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6438380&dopt=Abstract Naproxen Naprosyn





Arch Int Pharmacodyn Ther. 1993 Sep-Oct;325:113-28.
Plasma and tissue kinetics of phenylbutazone and naproxen in dogs.

Zech R, Scherkl R, Hashem A, Frey HH.

Department of Pharmacology and Toxicology, School of Veterinary Medicine, Freie Universitat Berlin, Germany.

By means of tissue cages in which a sterile inflammation was induced after injection of carrageenan, plasma and tissue kinetics of two NSAIDs were followed. The first one, phenylbutazone, is characterized by a fairly short elimination half-life (3-6 hours) in dogs, whereas the other one, naproxen, has an average half-life of 67 hours in this species. After a single oral dose of 15 mg/kg, phenylbutazone reached concentrations of 13-20 micrograms/ml in the exudate from the tissue cages. Plasma peak concentrations of 49-75 micrograms/ml were reached. Due to a considerably longer half-life in the exudate than in plasma (7.3-18 hours), the concentration in the exudate exceeded that in plasma at about 20 hours. Naproxen (5 mg/kg, orally) showed a parallel decline in plasma and exudate concentrations for more than 200 hours. Continued treatment for one week with phenylbutazone (15 mg/kg, BID) resulted in plasma concentrations with wide fluctuations between doses, but the concentration in the exudate remained at a constant level. After administration of naproxen (5 mg/kg on the first day and then 2 mg/kg once daily), plasma concentrations remained at 40-50 microgram/ml and those in the exudate at 20-30 microgram/ml throughout the treatment period. Both drugs caused a considerable fall of the leukocyte count in the exudate which may be used as an indicator of the anti-inflammatory effect.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8110026&dopt=Abstract Naproxen Naprosyn





Drug Metab Dispos. 1991 Sep-Oct;19(5):853-7.
Stereoselective disposition of carprofen, flunoxaprofen, and naproxen in rats.

Iwakawa S, Spahn H, Benet LZ, Lin ET.

Department of Pharmacy, University of California, San Francisco 94143-0446.

The stereoselective dispositions of carprofen, flunoxaprofen, and naproxen were studied in rats after i.v. administration of racemate (11 mumol/kg) or enantiomer (5.5 mumol/kg). The total clearances of the (R)-enantiomers of carprofen and flunoxaprofen were significantly greater than those of the (S)-enantiomers. The clearance of (S)-naproxen was similar to the value for (R)-naproxen. There were no marked differences in steady-state volume of distribution between (R)- and (S)-enantiomers for carprofen, flunoxaprofen, or naproxen. The (R)- to (S)-enantiomer inversion ratio for flunoxaprofen in rats was 0.54. The ratios for naproxen and carprofen were 0.02 and 0.003, respectively. Biliary excretion of (R)-carprofen and of its glucuronide were higher than those of the (S)-enantiomer and its glucuronide. In contrast, biliary excretion of the (S)-enantiomers of flunoxaprofen, naproxen, and of their glucuronides were greater than those of their antipodes. Insignificant amounts of the parent enantiomers and of the glucuronides of these three drugs were excreted in urine. These results indicate that there is a wide variation in the extent of inversion at a chiral center for these three 2-arylpropionates and in the stereoselective disposition of their acyl glucuronides.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1686227&dopt=Abstract Naproxen Naprosyn