The effect of multiple dosage on the kinetics of glucuronidation and sulphation of diflunisal in man.

Abstract

1 The single (250 and 500 mg) and multiple dose (250 and 500 mg twice daily for 15 days) pharmacokinetics of diflunisal were compared in young volunteers. 2 The plasma clearance of diflunisal was lowered significantly after multiple dose administration (5.2 ± 1.2 and 4.2 ± 0.7 ml min-' for the 250 and 500 mg twice daily regimens, respectively) as compared with single dose administration (11.4 ± 3.1 and 9.9 + 2.0 ml min-' for the 250 and 500 mg single doses, respectively).3 The partial metabolic clearances of diflunisal by acyl and phenolic glucuronide formation were lowered significantly (> 50%) after multiple dose administration. 4 The urinary recovery of diflunisal sulphate increased as a function of dose: 6.1 ± 2.8 and 9.1 ± 3.5% following the 250 and 500 mg single dose, respectively, and 10.9 ± 3.1 and 15.9 ± 3.6% following the 250 and 500 mg twice daily regimens. The partial metabolic clearance of diflunisal by sulphate conjugation was unchanged following multiple dose administration. 5 The plasma protein binding of diflunisal was concentration-dependent. Analysis of unbound plasma clearances of diflunisal showed that its total plasma clearance following 500 mg twice daily was affected by both saturable glucuronidation and concentrationdependent plasma binding.

Steady-state pharmacokinetics and tissue distribution of anthraquinones of Rhei Rhizoma in rats

“…The ratios of AUC of anthraquinone S to those of correspondent G/S following seven-dose administration were compared with those following single dose (Shia et al, 2009) and indicated that the ratios of S of aloe-emodin, rhein and emodin after sevendose administration of RP were increased by 744%, 144% and 460%. This phenomenon may stem from the saturated glucuronidation following multiple-dose administration like diflunisal (Verbeeck et al, 1990).…”

Effect of probenecid on the formation and elimination kinetics of the sulphate and glucuronide conjugates of diflunisal

“…Although biliary excretion of the diflunisal glucuronides was demonstrated in cholecystectomised patients with T-tube drainage, the results of that study indicate that it probably only contributes minimally to the overall elimination of the glucuronide conjugates in subjects with normal kidney function [34]. Diflunisal is highly bound to albumin in human plasma [35] and shows saturation of binding sites at plasma concentrations obtained following chronic administration of therapeutic doses of the drug [24].…”

“…Equilibrium dialysis was carried out as previously described [23,24]. For the in vitro experiments, plasma obtained from four healthy volunteers was pooled.…”

“…After gentle but thorough mixing the plasma samples were dialyzed as described in detail elsewhere [23,24]. A 1.2 ml aliquot of these plasma samples was pipetted into a 20 ml scintillation vial and approximately 3 ~tg radiolabelled diflunisal was added.…”

“…The present study has investigated the effect of probenecid on the pharmacokinetics of diflunisal, a compound forming a labile acyl glucuronide (DAG) and a stable phenolic glucuronide (DPG) [22][23][24]. Together the two glucuronidation pathways account for 60-80 % of the elimination of this compound.…”