Naproxen disposition in patients with alcoholic cirrhosis

Abstract

Chronic liver disease is known to alter the absorption and disposition of many drugs. To assess the influence of chronic alcoholic liver disease on the disposition of naproxen, we administered the drug both as a single dose and to steady state to 10 individuals with alcoholic cirrhosis and to 10 healthy controls. Plasma and serum samples collected after naproxen dosing were assayed for both total and (following equilibrium dialysis) unbound drug concentration. Clearance calculated based on both total and unbound naproxen concentration revealed no change in total plasma clearance of the drug at steady state but a marked reduction of approximately 60% in clearance based on unbound drug. Naproxen volume of distribution changed only minimally. Because clearance based on unbound drug concentration at a given dosing rate determines the plasma or blood free drug concentration, this concentration may increase significantly in patients with alcoholic liver disease given usual doses of naproxen. Unbound drug concentration is thought to determine the pharmacologic effect of a drug. We therefore recommend that naproxen dosing be reduced by at least half in patients with chronic alcoholic liver disease. In the absence of data to the contrary, this recommendation can be extended to individuals with other forms of hepatic disease.

Disposition kinetics of buspirone in patients with renal or hepatic impairment after administration of single and multiple doses

“…Alterations in serum protein binding [20][21][22][23], and a reduction in hepatic blood flow [24][25][26], as well as in the activity of metabolising enzymes [16,[26][27][28][29][30] in the liver of cirrhotic patients affect the disposition of drugs. Since the serum protein binding of buspirone and 1-PP is about 85 and 60 %, respectively, the volume of distribution and clearance are not likely to be significantly affected by any possible minor change in protein binding.…”

Naproxen pharmacokinetics in the elderly.

“…While the apparent reduction in intrinsic clearance of naproxen in the elderly may be due, in significant part, to diminished renal clearance of naproxen conjugates, additional factors may contribute. Subjects with hepatic impairment, specifically with Laennec's cirrhosis, have also been found to possess diminished intrinsic clearance of naproxen (Held, 1980;Williams et al, 1984). Determination of the relative contributions in the elderly of loss of hepatic-and loss of renal function is, however, tenuous in the absence of reasonably precise hepatic function measures and without better resolution of the confounding effects of protein binding and subject age in renal failure studies.…”

“…altered with impaired renal (Anttila et al, 1980) It is commonly used for treatment of both or hepatic function (Williams et al, 1984) and rheumatoid and osteo-arthritis and is thus fre-with changes in plasma protein (Williams et al, quently taken by the elderly. Several descrip-1984).…”

Effects of celecoxib and naproxen on renal function in nonazotemic patients with cirrhosis and ascites

“…31 Second, the observed peak concentrations of naproxen and celecoxib were within the range previously reported in patients with and without liver impairment in which effective inhibition of COX-1 or COX-2 was achieved. [32][33][34] Finally, we observed a significant suppression of platelet aggregation and ex vivo whole blood TXB 2 production after naproxen administration, indicating that this drug effectively inhibited COX-1 in platelets, and, presumably, in the kidney. Because platelets only have the COX-1 isoform, measurement of platelet function before and after treatment with NSAIDs is an established index of COX-1 inhibition.…”