Clin Biochem. 1979 Jun;12(3):100-3.
Determination of naproxen and its desmethyl metabolite in human plasma or serum by high performance liquid chromatography.

Slattery JT, Levy G.

1. A liquid chromatographic method has been developed for the simultaneous determination of the anti-inflammatory agent naproxen and its metabolite, 6-0-desmethyl-naproxen, in human plasma or serum. 2. After addition of p-chlorowarfarin as the internal stardard, plasma is acidified and extracted with either chloroform (for assay of naproxen only) or ethyl acetate (for assay of naproxen and desmethyl-naproxen), the organic solvent is evaporated, the residue is dissolved in acetonitrile and injected onto a reverse phase column coupled with an ultra-violet absorbance detector. 3. Drug and metabolite can be detected readily in concentrations above 2 micrograms per ml in 0.5 ml samples. Salicylic acid and its metabolites and a number of other durgs were found not to interfere with the assay.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=455634&dopt=Abstract Naproxen Naprosyn





J Gerontol. 1991 Nov;46(6):B222-7.
Age- and dose-dependent naproxen disposition in Fischer 344 rats.

Satterwhite JH, Boudinot FD.

College of Pharmacy, University of Georgia, Athens.

The effects of age and dose on the pharmacokinetics of naproxen were evaluated in young and senescent male Fischer 344 rats after 2.5 and 25 mg/kg doses. Pharmacokinetic parameters based on free naproxen concentrations demonstrated a significant decrease in free clearance and free steady-state volume of distribution in the aged rats. In vitro enzyme kinetic studies also demonstrated an age-related decline in the metabolic activity and affinity of the metabolic enzymes for naproxen in the aged rats. Plasma protein binding studies revealed a larger free fraction of drug in the plasma of senescent rats. Total clearance and steady-state volume of distribution were indistinguishable between young and old rats owing to the higher free fraction in aged rats. Dose had a significant effect with free clearance and free volume of distribution decreasing as dose increased. The binding of naproxen to plasma proteins was dependent on drug concentration. Unlike the parameters based on free naproxen concentrations, total plasma clearance and volume of distribution increased with increasing dose, due to the nonlinear protein binding.

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Br J Clin Pharmacol. 1993 May;35(5):467-72.
The pharmacokinetics of naproxen, its metabolite O-desmethylnaproxen, and their acyl glucuronides in humans. Effect of cimetidine.

Vree TB, Van Den Biggelaar-Martea M, Verwey-Van Wissen CP, Vree ML, Guelen PJ.

Department of Clinical Pharmacy, Academic Hospital Sint Radboud, Geert Grooteplein Zuid, Nijmegen, The Netherlands.

1. The pharmacokinetics of 500 mg naproxen given orally were described in 10 subjects using a direct h.p.l.c. analysis of the acyl glucuronide conjugates of naproxen and its metabolite O-desmethylnaproxen. 2. The mean elimination half-life of naproxen was 24.7 +/- 6.4 h (range 7 to 36 h). 3. Naproxen acyl glucuronide accounted for 50.8 +/- 7.3% of the dose recovered in the urine, its isomerised conjugate isoglucuronide for 6.5 +/- 2.0%, O-desmethylnaproxen acyl glucuronide for 14.3 +/- 3.4%, and its isoglucuronide for 5.5 +/- 1.3%. Naproxen and O-desmethylnaproxen were excreted in negligible amounts (< 1%). 4. Even though the urine pH of the subjects was kept acid in order to stabilize the acyl glucuronides, isomerisation took place in blood. 5. The extents of plasma binding of the unconjugated compounds were 98% (naproxen) and 100% (O-desmethylnaproxen), while naproxen acyl glucuronide binding was 92%; that of its isomer isoglucuronide 66%. O-desmethylnaproxen acyl glucuronide was 72% bound and its isoglucuronide was 42% bound. 6. Cimetidine (400 mg twice daily) decreased the t1/2 of naproxen by 39-60% (mean 47.3 +/- 11.5%; P = 0.0014) from 24.7 +/- 6.4 h to 13.2 +/- 1.0 h. It increased (10%) the urinary recovery of naproxen acyl glucuronide (P = 0.0492). The urinary recoveries of naproxen isoglucuronide and O-desmethylnaproxen acyl glucuronide remained unchanged.

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Am J Obstet Gynecol. 1981 Jul 1;140(5):592-8.
Naproxen sodium, aspirin, and placebo in primary dysmenorrhea. Reduction of pain and blood levels of prostaglandin F2-alpha metabolite.

Rosenwaks Z, Jones GS, Henzl MR, Dubin NH, Ghodgaonkar RB, Hoffman S.

In a double-blind, crossover study of 32 women with primary dysmenorrhea, the analgesic efficacy of naproxen sodium was compared to that of aspirin and placebo. The treatment started 1 to 5 days before the onset of menses and continued for 3 to 5 days. At the same time, a radioimmunoassay established concentrations of 13,14-dihydro-15-keto-prostaglandin F2-alpha, a prostaglandin F2-alpha metabolite (PGF-M) in blood samples obtained from before the treatment and on the first day of menses. In affording pain relief, naproxen sodium was superior to aspirin (p = 0.02) and placebo (p = 0.002); however, aspirin was not superior to placebo (p = 0.05). During naproxen sodium treatment, the patients' daily activities were less impaired than during both the aspirin and the placebo treatment courses. During naproxen sodium treatment, the mean blood PGF-M levels decreased by 73.5%, from a mean of 50.5 to 13.4 pg/ml; during aspirin treatment they decreased by 31.2%, from a mean of 44.2 to 30.4 pg/ml; during placebo treatment, an increase of 13.6% was observed, from a mean of 46.3 to 52.6 pg/ml. The PGF-M decrease during the naproxen sodium treatment was significantly more prominent than that during both aspirin and placebo treatments (p = 0.0001). Changes caused by aspirin treatment were significantly different from those occurring during the placebo treatment (p = 0.001). The study confirms that at the doses utilized in this study the analgesic properties of naproxen sodium are superior to those of the more conventional prostaglandin synthetase inhibitor, aspirin, and that pain relief is related to the inhibition of prostaglandin synthesis.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7246695&dopt=Abstract Naproxen Naprosyn





Ther Drug Monit. 1981;3(1):75-83.
Effect of Mylanta on naproxen bioavailability.

Weber SS, Bankhurst AD, Mroszczak E, Ding TL.

The effect of Mylanta on naproxen bioavailability was studied in 11 healthy volunteers. In separate experiments, single oral doses of naproxen (250 mg) and multiple oral doses (250 mg twice daily for 7 days) were administered with and without Mylanta. Coadministration of naproxen with Mylanta in the single-dose experiment did not significantly affect the area under the curve (579 vs. 580 microgram/ml X hr with and without Mylanta, respectively), time to peak serum concentration (2.5 vs. 2.6 hr), peak serum concentration (37.2 vs. 34.8 microgram/ml) or plasma half-life (16.1 vs. 16.4 hr). There was no significant difference between trough level naproxen concentrations at steady state (29.6 microgram/ml with Mylanta vs. 30.7 microgram/ml without Mylanta). The data were also used to investigate naproxen pharmacokinetics predicted by two different pharmacokinetic models, one of which allowed for protein binding. The nonlinear protein-binding model accurately predicted steady-state concentration, while the values predicted by the linear model exceeded actual values by 33-54%.

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Arzneimittelforschung. 1995 May;45(5):585-9.
Relationship between naproxen plasma concentration and its anti-inflammatory effect in experimental hepatitis.

Castaneda-Hernandez G, Favari L, Hoyo-Vadillo C.

Departamento de Farmcologia y Toxicologia, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Mexico City, Mexico.

The relationship between the plasma concentration and the anti-inflammatory effect of naproxen (CAS 22204-53-1) after oral administration of a 6 mg.kg-1 dose was studied in rats with galactosamine-induced acute hepatitis and under control conditions. In control animals naproxen peak plasma levels of 35 +/- 0.4 micrograms.ml-1 were reached in 0.5 +/- 0 h. Concentration then decayed, half-life being 5.2 +/- 0.4 h. AUC was 131 +/- 5 micrograms.h.ml-1. In intoxicated rats peak plasma levels of 29 +/- 0.3 micrograms.ml-1 were reached in 0.7 +/- 0.1 h, half-life was increased to 11.1 +/- 1.3 h, and the AUC reached 259 +/- 21 micrograms.h.ml-1. In control rats the protective effect of naproxen against carrageenan-induced inflammation increased slowly, reaching a maximum of 38% in 4 h. The protective effect against plasma concentration curve exhibited a clear counterclockwise hysteresis, probably due to a slow naproxen transport from the circulation to its site of action. In animals with hepatitis, the protective effect remained quite constant at about 40% despite variations in plasma levels, probably because the maximal effect was reached. No clear hysteresis was observed in the effect-plasma concentration curve, suggesting that naproxen arrival to its site of action was faster. Results show that the relationship between naproxen plasma concentration and its anti-inflammatory effect is complex and therefore predictions on the pharmacological response in liver damage cannot be readily made by solely considering pharmacokinetic data.

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Acta Physiol Hung. 1994;82(3):267-79.
Different effects of naproxen on the organ blood flows in normo- and hypervolemic anaesthetized rats.

Hably C, Borsos G, Bartha J.

Department of Physiology, Semmelweis University Medical School, Budapest, Hungary.

The effects of naproxen, an inhibitor of the enzyme cyclooxigenase (10 mg/kg i.v.) on the distribution of the cardiac output (CO) and on the intrarenal hemodynamics were investigated in normovolemic (free salt and water uptake till the beginning of experiment) and hypervolemic (with i.v. infusion of 50 ml 0.9% NaCl solution/kg/10 min) narcotized rats. The cardiac output was measured on the basis of he Stewart-Hamilton principle, the blood flow of the organs by the Sapirstein method. 86Rb was used as indicator. In hypervolemia, the blood pressure is the same, the cardiac output is higher (CO-normovolemia: 23.1 +/- 7.04, CO-hypervolemia: 29.0 +/- 6.43 ml/min/100 g; p < 0.05) the total peripheral resistance (TPR) is lower (TPR-normovolemia: 40.0 +/- 9.39 R, TPR-hypervolemia: 31.2 +/- 8.34 R, p < 0.05) than in normovolemic animals. In hypervolemia the vascular resistance of the investigated organs (heart, lungs, kidney, skin, muscle, liver, spleen, intestine) is also lower and the intrarenal blood flow shifts toward the medulla. One hour following the naproxen administration a) in normovolemia joining to a slightly decreased cardiac output and increased TPR, the vascular resistance of the skin (R-control: 85.1 +/- 32.7, R-naproxen: 161 +/- 57.4; p < 0.001) and of the skeletal muscle (R-control: 114 +/- 35.1, R-naproxen: 190 +/- 81.9; p < 0.01) increases. The blood flow of the other organs and the intrarenal hemodynamics does not change under the effect of naproxen. b) in hypervolemia the general circulatory parameters (blood pressure, cardiac output, TPR) and the parameters of the organ circulation and intrarenal hemodynamics remain unchanged. The results suggest that in rats the prostanoid compounds (PGE2, PGI2, TXA2) a) can modify the blood flow of the skin and muscle in normovolemic animals, but they do not have any role in determining the blood flow of the other organs or the intrarenal distribution of blood flow. b) in hypervolemia they play no role in determining organ-, or intrarenal blood flow. The consequences of cyclooxygenaze enzyme inhibition--at least in the case of the organ blood flow--depend on the magnitude of sodium and water load in the organism.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7717089&dopt=Abstract Naproxen Naprosyn