Naproxen pharmacokinetics

E. Samara, D. Avnir, D. Ladkani, M. Bialer, Pharmacokinetic Analysis of Diethyl-carbonate Prodrugs of Ibuprofen and Naproxen , Biopharm. Drug Dispos. 1995, 16, 201-210. 

Davies, N. M. and Anderson, K. E.. Clinical pharmacokinetics of naproxen, Clin. Pharmacokinet. 1997,... 

Melgert et al. studied the delivery of the corticosteroid dexamethasone to fibrotic livers [240], Dexamethasone has more potent and broader anti-inflammatory effects compared with naproxen. It inhibits the release of inflammatory mediators like TNF-a, IFN-y, and IL-6 and acts as an NFkB inhibitor [241, 242], Dexamethasone coupled to albumin (Dexa-HSA) was specifically taken up by sinusoidal cells in fibrotic rat livers, whereas dexamethasone itself was mainly taken up by hepatocytes. In vivo, Dexa-HSA promoted survival in endotoxin-induced liver inflammation in rats [240], In vitro, anti-inflammatory effects of the conjugate were measured in endotoxin-challenged liver slices. Dexa-HSA inhibited the release of nitric oxide and TNF-a in a dose-dependent manner (Melgert et al. unpublished data). To further enhance the delivery to KC at present dexamethasone is coupled to manHSA, and this conjugate is studied with respect to the pharmacokinetic profile and pharmacotherapeutic effects in fibrotic rats. 

While many aspects of nonlinear pharmacokinetic behavior may impact on the above equation, the more relevant pharmacokinetic processes for ASOs are absorption and distribution at or below therapeutic or nontoxic plasma concentrations. Nonlinear absorption or distribution processes can affect AUC terms in a nonproportional manner when different doses are compared, thereby resulting in an inaccurate determination of bioavailability. This has been shown to occur on numerous occasions for compounds such as ascorbic acid or naproxen [59-62]. Such cases require an understanding of the capacity-limiting cause of the nonlinearity and the pharmacokinetic processes upon which this impacts, in case of ASOs absorption and intercompartmental distribution processes from the central compartment into the peripheral tissues. With this understanding, various methods may then be applied to best approximate the rate of change of the plasma concentrations from one sampling time to the next allowing for an estimate of the absolute BAV. 

This chapter concentrates on some drug choices in acute rather than chronic pain, but the same principles can be used to determine the appropriateness of other types of analgesic. The drugs considered in this section are paracetamol, non-steroidal anti-inflammatories (NSAIDs specifically diclofenac, ibuprofen, indometacin, naproxen, sulindac and tenoxicam) and opioids (codeine, dihydrocodeine, morphine, pethidine and tramadol). Unless otherwise stated, all pharmacokinetic data originate from standard reference sources [1-5] and apply to adults only. 

In another trial the pharmacokinetics of a single dose of naproxen was studied in 11 patients with liver disease (four severe hepatitis with cholestasis two extrahepatic cholestasis one chronic alcoholic cirrhosis two active chronic hepatitis, with and without symptoms one asymptomatic PBC and one asymptomatic hepatic cirrhosis). In two of the seven patients with cholestasis, a significant delay in absorption occurred. In most of the patients studied there was a significant decrease in elimination, increasing the half-life from around 14 hours to 20 hours [41]. 

The 2-arylpropionic acid ( profen ) non-steroidal anti-inflammatory drugs, each of which contains a single chiral center, are formulated as racemic (50 50) mixtures of the S(+)- and R(-)-enantiomers, with the exception of naproxen, which is formulated as the S(- -)-enantiomer. Based on inhibition of cyclooxygenase activity, the S(- -)-enantiomer is the eutomer (more potent enantiomer). These drugs differ markedly in both pharmacodynamic activity and pharmacokinetic behavior and, in addition, enantiomer pharmacokinetics of each drug varies among animal species. After intravenous administration of racemic keto-profen to horses, sheep, and 20-week-old calves and measurement of individual enantiomers in plasma, significant differences between the enantiomers were found in systemic clearance in horses and in both systemic clearance and volume of distribution in sheep... 

Anttila M, Haataja M, Kasanen A. Pharmacokinetics of naproxen in subjects with normal and impaired renal function. Eur J Clin Pharmacol 1980 18(3) 263-8. 

Example Ibuprofen (Motrin, Advil, Nuprin) naproxen (Naprosyn) (Aleve is a similar OTC drug) Oxaprozin (Daypro) ketoprofen (Orudis). Route PO Pregnancy category B Pharmacokinetic Absorbed from the GI tract, metabolized in the liver and primarily excreted in urine ... 

Kunitani, M.G. Johnson, D.A. Upton, R.A. Riegelman, S. Convenient and sensitive high-performance liquid chromatography assay for cimetidine in plasma or urine. J.Chromatogr., 1981, 224, 156-161 [plasma urine non-interfering acebutolol, caffeine, ketoprofen, naproxen, theophylline pharmacokinetics LOQ 100 ng/mL]... 

Schmitt, M. Guentert, T.W. Biopharmaceutical evaluation of ketoprofen following intravenous, oral, and rectal administration in dogs. J.Pharm.Sci., 1990, 79, 614-616 [plasma dog naproxen (IS) pharmacokinetics]... 

Samara, E. Avoir, D. Ladkani, D. Bialer, M. Pharmacokinetic analysis of diethylcarbonate prodrugs of ibuprofen and naproxen. Biopharm.Drug Dispos., 1995, 16, 201-210... 

Lafontaine, D. Mailhot, C. Vermeulen, M. Bissonnette, B. Lambert, C. Influence of chewable sucralfate or a standard meal on the bioavailability of naproxen. Clin.Pharm., 1990, 9, 773-777 [pharmacokinetics LOQ 1 pg/mL diphenylacetic acid (IS)]... 

Satterwhite, J.H. Boudinot, F.D. High-performance liquid chromatographic determination of ketoprofen and naproxen in rat plasma. J.Chromatogr, 1988, 431, 444-449 [ketoprofen (IS) LOD 5 ng/mL pharmacokinetics]... 

Celecoxib is currently indicated for the relief of signs and symptoms of osteoarthritis and rheumatoid arthritis and to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis as an adjunct to usual care. Celecoxib is at least as effective as naproxen in the symptomatic management of osteoarthritis and at least as effective as naproxen and diclofenac in the symptomatic treatment of rheumatoid arthritis, and it is less likely to cause adverse Gl effects. Celecoxib appears to be effective in the management of pain associated with both of these arthritic conditions, but effectiveness in acute or chronic pain has not been fully demonstrated. Unlike aspirin, celecoxib does not exhibit antiplatelet activity. Concomitant administration of aspirin and celecoxib may increase the incidence of Gl side effects. Another notable potential drug interaction with celecoxib is its ability, like other NSAIDs, to reduce the blood pressure response to angiotensin-converting enzyme inhibitors. A more detailed discussion of the chemical, pharmacological, pharmacokinetic, and clinical aspects of celecoxib is available (81). 

C. Pharmacokinetics. NSAIDs are generally well absorbed, and volumes of distribution (Vd) are relatively small (eg, 0.15 L/kg for ibuprofen). COX-2 inhibitors have larger volumes of distribution (86-91 L in adults for rofecoxib, 400 L for celecoxib). Most agents are highly protein bound, and most are eliminated through hepatic metabolism and renal excretion with variable half-lives (eg, 1.5-2.5 hours for ibuprofen and 12-17 hours for naproxen). (See also Table 11-59.)... 

Aspirin 1.3 to 3.6 g daily more than halved the serum levels of ibuprofen 800 mg to 2.4 g daily, without affecting salicylate levels. There was little additional clinical benefit from the combination. Similarly, aspirin reduced the AUC of flurbiprofen by about two-thirds, but without any clear changes in clinical effectiveness. The pharmacokinetics of the aspirin were unchanged by flurbiprofen. Aspirin 3.9 g daily also virtually halved the AUC of fenoprofen 2.4 g daily,and reduced the AUC of ke-toprofen 200 mg daily by about one-third. The AUC of naproxen was only minimally reduced (by 10 to 15%). Choline magnesium trisalicylate increased the clearance of naproxen by 56% and decreased its serum levels by 26% in one study. ... 

Naproxen. Food did not have any clinically relevant effect on the pharmacokinetics of sustained-release naproxen in two studies. Taking a single 550-mg dose of naproxen sodium with a meal had no effect on its analgesic efficacy in postoperative pain, when compared with the fasted state. However, the rate of absorption of a single 550-mg dose of S-naproxen betainate sodium salt monohydrate was found to be reduced by a high-fat meal, when compared with the fasting state. ... 

One study found no adverse interaction between naproxen and cimetidine and no alteration in the beneficial effects of cimeti ne on gastric acid secretion, but another study found that cimetidine caused a moderate 39 to 60% decrease in the naproxen half-life, and a 20 /o reduction in the AUC of naproxen. In one of these studies the half-life of naproxen was reduced by about 40% by ranitidine and 50% by famotidine. A further study found that nizatidine does not affect the pharmacokinetics of naproxen. ... 

Holford NHG, Altaian D, Riegelman S, Buskin JN, Upton RA. Pharmacokinetic and pharmacodynamic study of cimetichne administered with naproxen. Clin Pharmacol Ther 9% ) 29, 251-2. 

Vree TB, van den Biggelaar-Martea M, Verwey-van Wissen CPWGM, Vree ML, Guelen PJM. The pharmacokinetics of naproxen, its metabolite 0-desmethylnaproxen, andtiieir acyl glucuronides in humans. Effect of cimetidine. BrJ Clin Pharmacol (1993) 35, 467-72. 

The concurrent use of two or more NSAIDs increases the risk of gastrointestinai damage. Diflunisal raises serum indometacin levels about twofold but does not affect naproxen levels. The concurrent use of indometacin and flurbiprofen does not appear to affect the pharmacokinetics of either drug. Floctafenine does not alter diclofenac levels. Indometacin caused renal impairment in a patient recovering from phenylbutazone-induced acute renal failure. 

Misoprostol increases the incidence of abdominal pain and diarrhoea when used with diclofenac or indometacin. Isolated cases of neurological adverse effects have been seen with naproxen or phenylbutazone given with misoprostol. However, no important pharmacokinetic interactions seem to occur between aspirin, diclofenac, ibuprofen or indometacin and misoprostol. NSAIDs are reported not to affect the abortive effects of intravaginal misoprostol. 

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