FACTORS AFFECTING THE DISPOSITION OF DIFILUNISAL AND ITS METABOLITES.
Date
1990
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Degree Level
Doctoral
Abstract
Diflunisal is a nonsteroidal anti-inflammatory drug used in the treatment of arthritis and musculoskeletal pain. Diflunisal is mainly eliminated by metabolism. Non-linear elimination and saturable plasma protein binding of diflunisal in humans is well recognized. The non-linear elimination of diflunisal is a result of saturation of the formation of diflunisal acyl glucuronide (DG) following administration of increasing single doses (100 - 1000 mg) and the saturation of both acyl and phenolic glucuronide (DG) pathways following multiple doses (250 mg to 500 mg twice daily).
The objective of this study was to examine the effect of physiologic (male vs females), pathologic (cirrhosis) and pharmacologic (smoking, OCS and paid) factors, known to have an impact on conjugation, on the pharmacokinetics of diflunisal The studies were designed to examine the effect of these factors on the total clearance of difliaiisal and to determine if there are any differential effects on specific metabolic pathways.
High performance liquid chromatography (HPLC) assays were developed to analyze diflunisal and its conjugates in urine and plasma. The plasma protein binding of diflunisal was determined both in vitro and ex vivo using equilibrium dialysis.
In an attempt to improve the chromatographic properties of the diflunisal sulphate conjugate (DS), the analytical HPIC assay of Loewen et al (1989) was modified by adding anhydrous Na2SO4 (0.0]M) to the aqueous nubile phase. With Na2SO4 in the mobile phase, a new peak appeared on the chromatogram of urine samples. Although the material could be isolated, it was too unstable to identify by mass spectrometry The unidentified material was isolated and hydrolyzed by ether extraction. The hydrolysis product was identified by mass spectrometry and NMR spectroscopy as 3 hydroxy diflunisal. The unidentified peak seen on chromatography of urine samples is thought to be a conjugate of this 3 hydroxy metabolite. The metabolic importance of the 3-hydroxy metabolite of diflunisal has not been determined, although smoking may induce this metabolic pathway.
The effect of cirrhosis on the disposition of diflunisal was examined in 5 cirrhosis patients and 5 sex and age matched controls. The apparent volume of distribution, the elimination half-life and total clearance of diflunisal were unaltered by cirrhosis. The intrinsic ability of the liver to glucuronidate diflunisal seemed to be reduced in cirrhosis, whereas sulphation remained unchanged. The percent unbound of diflunisal was increased in cirrhosis (0.073 to 0.121%). The reduction in glucuronidation capacity appeared to be offset by an increase in the free fraction of diflunisal in cirrhosis, resulting in no overall change in clearance.
Description
Keywords
Difunisal
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Pharmacy