Nonlinear plasma level response to high doses of naproxen

Runkel, Richard; Forchielli, Enrico; Sevelius, Hilli; Chaplin, M. D.; Segre, Eugene J.

doi:10.1002/cpt1974153261

Cited by 116 publications

(32 citation statements)

References 1 publication

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“…AUC (45). The plateau effect is attributed to saturation of protein binding sites, resulting in more unbound drug that can be cleared by the kidney, and may represent a selfregulatory mechanism that limits plasma levels and thus toxicity (45).…”

Section: Discussionmentioning

confidence: 99%

Renal Changes Associated with Naproxen Sodium Administration in Cynomolgus Monkeys

Leach¹,

Frank²,

Berardi³

et al. 1999

Toxicol Pathol

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Naproxen sodium was administered to cynomolgus monkeys (Macaca fascicularis) by oral gavage at daily doses of 44, 88, or 176 mg/kg for 2 wk (2 monkeys/gender) or of 44 mg/kg for 13 wk (4 monkeys/gender). Body weight loss occurred in at least one monkey in all naproxen sodium-dosed groups in the 2-wk (up to 16% loss) and 13-wk (up to 22% loss) studies. Increases in plasma naproxen concentrations were dose proportional between 44 and 88 mg/kg but were less than dose proportional between 88 and 176 mg/kg. Up to 2-fold increases in creatinine and/or serum urea nitrogen values as well as higher renal weights occurred in monkeys receiving 176 mg/kg for 2 wk or 44 mg/kg for 13 wk. Microscopically, renal changes were observed in all naproxen sodium-dosed groups. Renal findings after 2 wk of exposure included increased interstitial ground substance, tubular dilatation, and tubulointerstitial nephritis; in the 13-wk study, cortical tubular atrophy and interstitial fibrosis were also observed. These studies identify the kidney as the target organ of naproxen sodium in cynomolgus monkeys.

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Section: Discussionmentioning

confidence: 99%

Renal Changes Associated with Naproxen Sodium Administration in Cynomolgus Monkeys

Leach¹,

Frank²,

Berardi³

et al. 1999

Toxicol Pathol

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“…In healthy volunteers naproxen absorption after oral administration of a single dose up to 4000 mg is nearly complete. However, non-linear, decreasing increments of AUC have been observed upon administration of subsequent larger doses, probably due to saturation of albumin binding (Runkel et al, 1974(Runkel et al, , 1976.…”

Section: Discussionmentioning

confidence: 99%

Naproxen pharmacokinetics in patients with rheumatoid arthritis during active polyarticular inflammation.

Ouweland

Franssen

Putte

et al. 1987

Brit J Clinical Pharma

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1 Patients with rheumatoid arthritis often have hypoalbuminaemia as a sign of disease activity. In view of the extensive binding of naproxen to albumin, the pharmacokinetics of total and unbound drug were studied in eight patients and eight healthy male volunteers during chronic intake of 500 mg twice daily. 2 The area under the serum concentration-time curve of total naproxen during a dose interval, AUC (0,12), was smaller in patients (641 ± 101 mg 1-1 h) than in volunteers (896 + 85 mg 1-1 h; P < 0.0001). The unbound naproxen AUCu (0,12) was larger in patients (1.9 ± 0.9 mg 1-1 h) than in volunteers (0.7 ± 0.2 mg 1-1 h; P < 0.01). 3 The higher unbound naproxen concentrations in patients were accompanied by an approxmately 40% increase in apparent clearance/bioavailability (CL/F) and a 60% increase in volume of distribution (VIF). 4 Both CL/F and VIF were inversely correlated with the individual serum albumin concentration (r = 0.76, P < 0.001; r = -0.85, P < 0.001, respectively). 5 The high unbound naproxen concentration in the serum of patients with active rheumatoid arthritis and concomitant hypoalbuminaemia is not known to be accompanied by an increase in side effects and may be beneficial if anti-inflammatory effects correlate with unbound drug concentration.

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“…These experiments very strongly suggest that it is the protein binding of drug to the BSA that renders the drug inaccessible to the cell and that the binding may be considered as competitive since higher doses of drug appear to overcome the diminished inhibitory effect. It has been shown that naproxen and phenylbutazone when administered to test subjects is 98% bound to plasma proteins [3,4] and 82% of the administered dose of niflumic acid is bound to plasma protein [5].…”

Section: Discussionmentioning

confidence: 99%

The effect of bovine serum albumin on the in vitro inhibition of chemotaxis by anti-inflammatory agents

Rivkin¹

1977

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The anti-inflammatory agents, phenylbutazone, naproxen and niflumic acid inhibited in vitro rabbit peritoneal neutrophil chemotactic responsiveness to Escherichia coli derived chemotactic factor/s when added to cells suspended in 0.1% bovine serum albumin (BSA). Inhibition of chemotaxis by these drugs was markedly diminished as the BSA concentration was increased to 2%. Experiments with phenylbutazone demonstrated that inhibition of chemotaxis could be observed using neutrophils suspended in 2% BSA by either increasing the drug concentration or by preincubating the cells suspended in 0.1% with the drug prior to the addition of the additional BSA. These data suggest that protein binding can prevent in vitro inhibition of neutrophil chemotaxis by anti-inflammatory agents.

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Nonlinear plasma level response to high doses of naproxen

Cited by 116 publications

References 1 publication

Renal Changes Associated with Naproxen Sodium Administration in Cynomolgus Monkeys

Renal Changes Associated with Naproxen Sodium Administration in Cynomolgus Monkeys

Naproxen pharmacokinetics in patients with rheumatoid arthritis during active polyarticular inflammation.

The effect of bovine serum albumin on the in vitro inhibition of chemotaxis by anti-inflammatory agents

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