Diflunisal glucuronides

Diflunisal 250 mg twice daily for 7 days given with sodium valproate 200 mg twice daily caused a 20% increase in the unbound fraction of valproate in 7 healthy subjects. There was a 35% increase in the AUC of one of the oxidation metabolites of valproate, and a small decrease in the AUC of some of the diflunisal glucuronide metabolites. This was shown to be due to changes in renal clearance of these metabolites. Whether any of these modest changes have any clinical relevance remains to be seen, but it appears unlikely. 

R. G. Dickinson, A. R. King, Reactivity Considerations in the Analysis of Glucuronide and Sulfate Conjugates of Diflunisal , Then Drug Monit. 1989, 11, 712 - 720. 

F. M. Brunelle, P. K. Verbeeck, Conjugation-Deconjugation Cycling of Diflunisal via Beta-Glucuronidase Catalyzed Hydrolysis of Its Acyl Glucuronide in the Rat , Life Sci. 

M. Wang, R. G. Dickinson, Disposition and Covalent Binding of Diflunisal and Diflunisal Acyl Glucuronide in the Isolated Perfused Rat Liver , Drug Metab. Dispos. 1998, 26, 98 - 104. 

Peak plasma concentrations are reached within 2 to 3 h after oral dosing. Diflunisal is heavily bound to plasma protein (>99 %), has a long elimination half-life (8-12 h) and non-linear kinetics. Hence, it is used with an initial loading dose (1000 mg) and a lower maintenance dose (500-1000 mg/day). Diflusinal is excreted as glucuronide in the urine. 

J. Hansen-Moeller, C. Cornett, L. Dalgaard, and S. H. Hansen, Isolation and identification of the rearrangement products of diflunisal 1-O-acyl glucuronide, J. Pharm. Biomed. Anal., 6 (1988) 229-240. 

Probenecid Diflunisal Formation CL of phenol glucuronide and acyl glucuronide decreased 45% and 54%, respectively 114... 

Induction of the glucuronidation of several drugs, including lamotrigine by oral contraceptive steroids (OCSs), has been observed (134). The formation clearance to the acyl glucuronide of diflunisal increased from 3.01 mL/min in... 

Mano Y, Usui T, Kamimura H. In vitro drug interaction between diflunisal and indomethacin via glucuronidation in humans. Biopharm Drug Dispos 2006 27 267-273. 

Wang, M. and Dickinson, R.G., Disposition and covalent binding of diflunisal and diflunisal acyl glucuronide in the isolated perfused rat liver, Drug Metab. Disposition, 26, 98-104, 1998. 

Diflunisal is a fluorinated salicyhc acid derivative, which is absorbed unchanged from the gastrointestinal tract, reaching peak concentrations after about 2 hours, and is metabolized by glucuronidation (1). Its adverse effects and other characteristics are those of aspirin, although gastrointestinal haemorrhage may be less common (2). 

V. Glucuronide-derived Covalent Binding of Diflunisal to Bladder Tissue of Rats and Its Modulation by Urinary pH and Beta-glucuronidase," Biochem. Pharmacol. 46(7), 1175-1182 (1993). 

Diflunisal (dolobid) is a difluorophenyl derivative of salicylic acid (Figure 26-1). It is almost completely absorbed after oral administration, and peak plasma concentrations occur within 2-3 hours. It is extensively bound to plasma albumin (99%). About 90% of the drug is excreted as glucuronide conjugates, and its rate of elimination is dose-dependent. At the usual analgesic dose (500-750 mg/day), the plasma averages 8-12 hours. Diflunisal appears in the milk of lactating women. 

Other important metabolites of O-glucuronidation are acylglucuronides. They are formed by esterification of carboxylic acids with glucuronic acid. Many therapeutic agents such as arylacetic acids (diclofenac, diflunisal), aliphatic acids (valproic acid) and arylpropionic acids (ketoprofen, naproxen) are metabolized as acylglucuronides (Fig. 31.37). 

Fig. 31.37 Substrates that form reactive glucuronides (1) ketoprofen (2) naproxen (3) clofibric acid (4) diclofenac (5) diflunisal (6) valproic acid (7) all-frans retinoic acid (8) bilirubin (9) A/-hydroxy-2-acetyTaminofluorene.

The damaging effects of the NSAIDs on the gut appear to be additive. Diflunisal may inhibit the glucuronidation of indometacin, or could compete for renal clearance of unmetabolised indometacin. All NSAIDs have the propensity to cause renal impairment. 

In 8 healthy subjects probenecid 500 mg twice daily increased the steady-state plasma levels of diflunisal 250 mg twice daily by 65%, and reduced the clearances of the glucuronide metabolites. ... 

Macdonald JI, Wallace SM, Herman RJ, VerbeeckRK. Effect of probenecid on the farmation and elimination kinetics of the sulphate and glucuronide conjugates of diflunisal. EurJ CUn Pharmacol (1995) 47,519-23. 

Dickinson, R.G. King, A.R. Reactivity considerations in the analysis of glucuronide and sulphate conjugates of diflunisal. Ther. Drug. Monit. 1989, 77 (6), 712 720. 

The ester glucuronide (7) of diflunisal was found to be unstable particularly in neutral or basic solution, nine rearrangement or degradation products being detected by reversed-phase ion-pair riPLC. The full paper on heterogeneous catalytic transfer hydro-... 

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