Diflunisal and its conjugates in patients with renal failure.

Abstract

Six patients with renal failure were given a single oral dose (250 mg) of diflunisal. In contrast to the acyl glucuronide, the phenolic glucuronide and sulphate conjugates showed the capacity to accumulate in plasma, suggesting that systemic instability of the acyl glucuronide contributes, via hydrolysis, to plasma concentrations of diflunisal itself. Although earlier studies in renal failure patients have almost certainly underestimated diflunisal clearance (by overestimation of plasma diflunisal concentrations through unrecognized acidic hydrolysis of diflunisal sulphate during analysis), the present results suggest that the reported decrease in clearance was not attributable only to this analytical artifact.

Studies on the renal excretion of the acyl glucuronide, phenolic glucuronide and sulphate conjugates of diflunisal.

“…Values for CLR of DF itself (Table 1), although somewhat smaller than those reported earlier in healthy volunteers (Balali-Mood & Prescott, 1989;Verbeeck et al, 1990) are probably still overestimates because of probable small contributions to urinary DF concentrations from hydrolysis of DAG during urine retention in the bladder and perhaps of DS during acidic workup for analysis (Dickinson et al, 1991b). Even a relatively trivial amount of conjugate hydrolysis would cause a substantial increase in the apparent amount of DF excreted in urine.…”

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

“…Because of interference by probenecid metabolites in the analysis of the sulphate conjugate in urine, they could not calculate the renal clearance of DS. A study with diflunisal in patients with renal failure, however, showed accumulation in plasma of the stable sulphate conjugate and phenolic glucuronide, whereas the plasma concentrations of the acyl glucuronide were very low, probably due to systemic hydrolysis [37]. The renal clearance of diflunisal itself is very small and it may be overestimated because of the facile but variable (due to variations in urine pH and residence time in the bladder) hydrolysis of DAG during urine retention in the bladder.…”

Mechanism of sulfotransferase pharmacogenetics in altered xenobiotic metabolism

“…Paracetamol combined with opioid sulfate analgesics, such as morphine, naltrexone, naloxone and buprenorphine [11,12], is used in managing severe pain such as postsurgical pain and providing palliative care in advanced cancer patients [13]. The other SULT drug substrates, such as diflunisal, are used as analgesics and anti-inflammatory drugs [14]. Budesonide is used as an anti-inflammatory corticosteroid [15].…”