Biochem Pharmacol. 1993 Oct 5;46(7):1298-300.
Stereoselective glucuronidation of (R)- and (S)-naproxen by recombinant rat phenol UDP-glucuronosyltransferase (UGT1A1) and its human orthologue.

el Mouelhi M, Beck S, Bock KW.

Institute of Toxicology, University of Tubingen, Germany.

Recombinant rat phenol UDP-glucuronosyltransferase (UGT1A1) conjugates (R)-naproxen at a much higher rate (> 17-fold) than its (S)-enantiomer, substantiating previous findings on stereoselective glucuronidation of racemic naproxen. In contrast, the recombinant human orthologue conjugated both enantiomers at equal rates. In line with high constitutive expression of UGT1A1 in extrahepatic tissues, a high R/S ratio of naproxen glucuronidation was found in rat testes, intestine, lung and kidney. The results demonstrate that (R)-naproxen represents a stereoselective substrate of rat UGT1A1, but not of the human orthologous UGT1A1.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8216382&dopt=Abstract Naproxen Naprosyn





Gen Pharmacol. 1995 Jan;26(1):211-8.
Naproxen inhibits hepatic glycogenolysis induced by Ca(2+)-dependent agents.

Nascimento EA, Yamamoto NS, Bracht A, Ishii-Iwamoto EL.

Department of Biochemistry, University of Maringa, Brazil.

1. The non-steroidal anti-inflammatory naproxen inhibited steady-state glycogenolysis stimulation caused by norepinephrine, phenylephrine (alpha 1-agonists) and methotrexate (not receptor mediated) in the isolated perfused rat liver. Stimulation of glycogenolysis caused by these agents is Ca(2+)-dependent. 2. Naproxen did not inhibit glycogenolysis stimulation caused by glucagon. 3. The action of naproxen depended on the extracellular Ca2+ concentration. At 0.25 mM extracellular Ca2+, the norepinephrine stimulated glycogenolysis was inhibited by 60% by 0.5 mM naproxen. At 3.5 mM Ca2+, inhibition was reduced to 25%. The inhibition degree correlated linearly with the extracellular Ca2+ concentration. 4. 45Ca2+ efflux stimulation caused by norepinephrine was not affected by naproxen, indicating that the mobilization of the intracellular Ca2+ pools was not significantly affected by naproxen. The initial increases in glycogenolysis caused by norepinephrine in the absence of extracellular Ca2+ (pre steady-state) were not affected by naproxen. These increases depend on intracellular Ca2+ mobilization. 5. It can be concluded that the action of naproxen is most probably related to the cytosolic Ca2+ concentration which, under steady-state conditions, depends on the extracellular one during the action of Ca(2+)-dependent glycogenolytic agents.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7713362&dopt=Abstract Naproxen Naprosyn





Pharmacology. 1995 May;50(5):324-32.
Calcium-and G-protein-related spasmolytic effects of nonsteroidal anti-inflammatory drugs on rat uterus contractions in vitro.

Perez Vallina JR, Cantabrana B, Hidalgo A.

Laboratorio de Farmacologia, Departamento de Medicina, Facultad de Medicina, Oviedo, Spain.

The effects of the nonsteroidal anti-inflammatory drugs (NSAIDs) acetylsalicylic acid, metamizole, phenylbutazone, indometacin, piroxicam, naproxen, tolmetin, diclofenac, and mefenamic acid on methacholine (10 mumol/l), prostaglandin F2 alpha (1 mumol/l), and KCl (60 mmol/l) induced contractions of isolated rat uterus were assayed. All of these cause a concentration-dependent inhibition of methacholine and prostaglandin F2 alpha-induced contractions with the exception of acetylsalicylic acid, metamizole, and naproxen. All except acetylsalicylic acid and metamizole relaxed in a concentration-dependent manner the tonic contractions induced by KCl. CaCl2 (0.1-10 mmol/l) totally counteracted the relaxant effects of naproxen and tolmetin, but not those of the other NSAIDs. Bay K8644 did not revert the effect of the NSAIDs. Pertussis toxin (50 micrograms/l) did not modify the effect of indometacin, mefenamic acid, and tolmetin, but partially antagonized the effects of diclofenac and naproxen and increased the effect of phenylbutazone and piroxicam. These results suggest that some of the NSAIDs assayed induce smooth muscle relaxation by mechanisms independent of prostaglandin synthesis inhibition, but related to the inhibition of extracellular calcium influx through mechanisms related or unrelated to pertussis toxin sensible G proteins.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7545306&dopt=Abstract Naproxen Naprosyn





J Pharm Sci. 1990 May;79(5):389-92.
Effects of various granulating systems on the bioavailability of naproxen sodium from polymeric matrix tablets.

Dahl T, Ling T, Yee J, Bormeth A.

Institute of Pharmaceutical Sciences, Syntex Research, Palo Alto, CA 94304.

Naproxen sodium and a cellulose ether derivative were granulated with either water or a poly(meth)acrylic acid ester copolymer aqueous dispersion to make three controlled-release matrix dosage forms. The different polymeric matrix systems contained hydroxypropyl methylcellulose (formulation A), hydroxypropyl cellulose:poly(meth)acrylic acid ester copolymer (formulation B), and hydroxypropyl methylcellulose:poly(meth)acrylic acid ester copolymer (formulation C). All three hydrophilic matrix tablets demonstrated identical in vitro dissolution rates. The three controlled-release formulations were compared with a marketed immediate-release naproxen sodium dosage form (formulation D) in a single-dose crossover study in six healthy volunteers. The AUC values for controlled-release dosage forms A and C were larger than those for formulations B and D. However, the reasons why the AUC for formulations A and C is larger than that for formulations B versus D can be explained differently. Formulations A and C more effectively maintain naproxen plasma levels than formulation D by reducing the amount of naproxen unbound to plasma proteins, therefore reducing naproxen available for urinary excretion. Naproxen sodium delivered from formulations A and C is also probably much better absorbed than from that from formulation B, possibly due to less drug entrapment. More importantly, although all three CR formulations had identical in vitro dissolution profiles, naproxen sodium plasma levels were better maintained (based on AUC) in subjects taking formulations A and C, which contained a lower polymer content and did not use hydroxypropyl cellulose. The tmax values were larger for the three controlled-release dosage forms. Also, the Cmax value for the conventional dosage form was nearly twofold higher than that observed for the controlled-release dosage forms.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2352155&dopt=Abstract Naproxen Naprosyn





Int J Clin Pharmacol Ther Toxicol. 1988 Mar;26(3):143-7.
Pharmacokinetics of high-dosage naproxen in elderly patients.

Van den Ouweland FA, Jansen PA, Tan Y, Van de Putte LB, Van Ginneken CA, Gribnau FW.

Institute of Pharmacology, University Hospital St. Radboud, Nijmegen, The Netherlands.

After multiple oral doses of 500 mg naproxen twice daily, eight young healthy male volunteers and six male and female elderly patients participated in a pharmacokinetic study. Serum naproxen levels were measured by high-pressure liquid chromatography; protein-unbound drug was determined after equilibrium dialysis. A significantly lower maximal serum concentration (Cpeak), smaller area under the curve during one dose interval [AUC(0-12)], larger total body clearance (CL/F) and apparent volume of distribution (V/F body wt-1) were found for the total drug in elderly patients. The pharmacokinetics of the protein-unbound drug showed higher trough and peak concentrations, larger AUC(0-12)u, and smaller (CL/F)u and (V/F)u in the elderly patients. The unbound fraction (less than 1% of total naproxen) showed concentration dependency; in the elderly, a larger unbound fraction was found. Pharmacokinetic differences between the elderly and the young may be explained by a lower serum albumin concentration in the aged, together with a decrement in binding affinity of naproxen to albumin; moreover, the clearance of unbound drug was significantly reduced in the elderly (281 +/- 96 l/h) as compared with the young (713 +/- 164 l/h). We conclude that age-related factors increase serum unbound naproxen concentrations. It is, therefore, advisable to start treatment with naproxen in the elderly at a low dosage.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3410597&dopt=Abstract Naproxen Naprosyn





Bone Miner. 1994 Jul;26(1):43-59.
Cancellous bone behavior in hindlimb immobilized rats during and after naproxen treatment.

Lane N, Maeda H, Cullen DM, Kimmel DB.

Division of Rheumatology, University of California at San Francisco 94143.

Temporary immobilization creates bone loss. The purpose of this investigation was to use an agent to protect the skeleton from bone loss bone during temporary immobilization. Eighty-nine 6-month-old retired breeder Sprague-Dawley female rats were used. Animals were randomly divided into six groups of equal numbers. Four groups were given drinking water from day 0, containing naproxen (100 or 200 mg/l). At day 7, half the animals in all groups had their right hindlimb immobilized. At day 49, half the immobilized rats and non-immobilized controls were sacrificed. The remaining rats were remobilized and the drug was stopped. At day 91, all remaining rats were sacrificed. Gastrocnemius and soleus muscle weights were determined. Right tibiae were analyzed for cancellous bone mass, bone structural and bone dynamic variables. At the close of immobilization, bone mass was lower in the right (immobilized) hindlimb of the immobilized group than in the non-immobilized group. Immobilized rats drinking 100 mg/l naproxen water had significantly higher bone mass in their immobilized limbs than did untreated immobilized rats, but all rats drinking 200 mg/l naproxen water had lower bone mass than controls. After 6 weeks of recovery, bone mass in the immobilized limb of untreated formerly immobilized rats improved, but remained below untreated never-immobilized rats. Formerly immobilized rats that had been treated with 100 mg/l naproxen water had normal bone mass after 6 weeks of recovery. Naproxen, an agent that mildly depresses activation frequency, prevents some of the transient bone mass and structural deterioration during temporary immobilization. Such treatment facilitates a more rapid return to normal bone mass, though not to normal structure. The more rapid recovery occurs because the difference from normal is less, not because of more rapid formation in recovering animals.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7950504&dopt=Abstract Naproxen Naprosyn





South Med J. 1977 May;70(5):562-4.
Acute erosive gastritis induced by aspirin, ketoprofen, ibuprofen, and naproxen: its prevention by metiamide and cimetidine.

Mann NS, Sachdev AJ.

Aspirin, ketoprofen, ibuprofen, and naproxen all produced acute gastric erosions in rats. Aspirin produced significantly more erosions than ketoprofen, ibuprofen, or naproxen. There was no significant difference between the effects of ketoprofen, ibuprofen, and naproxen. Aspirin and naproxen produced a synergistic effect at higher dosage. Metiamide and cimetidine were effective in preventing this type of experimental acute erosive gastritis.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16348&dopt=Abstract Naproxen Naprosyn