Limited capacity for salicyl phenolic glucuronide formation and its effect on the kinetics of salicylate elimination in man

1Nine patients with rheumatoid arthritis or non-inflammatory backache were given soluble aspirin (65 mg/kg body weight) daily. There was no significant difference between the plasma salicylate of those with rheumatoid arthritis and those with backache. 2 Two patients had plasma salicylate values that differed significantly from the remainder but neither these results nor the marginal differences between plasma salicylate levels of the others could be explained by individual variations in the capacity for excreting salicyluric acid or salicyl phenolic glucuronide. 3 Increasing the dose of aspirin in four patients demonstrated the reduced proportions of salicyluric acid and salicyl phenolic glucuronide excreted at high doses and the increased importance of unchanged salicylic acid as an excretory pathway. These findings are consistent with a limiting capacity for salicyluric acid and salicyl phenolic glucuronide synthesis and excretion. 4 The findings in one patient suggested that inter-subject variations in the capacity for producing salicyl phenolic glucuronide and salicyluric acid may have an effect on plasma salicylate levels at high doses of aspirin.

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Kinetics of salicylate metabolism.

Gibson¹,

Zaphiropoulos²,

Grove³

et al. 1975

“…These cited observations support our interpretation for the present findings which indicate that elimination of diflunisal for plasma is capacitylimited. In addition, pharmacokinetic studies with sodium salicylate, a compound possessing a chemical structure very close to that of diflunisal, have clearly demonstrated that man has a lmited capacity for salicyl phenolic glucuronide formation even within the therapeutic dose range (Levy & Procknal, 1968;Levy, Tsuchiya & Amsel, 1972), whereas salicyl acyl glucuronide formation is known to involve an apparent first-order process (Levy et al, 1972). Based on the above considerations, it is thus very likely that formation of 5-(2', 4'-difluorophenyl) salicyl phenolic glucuronide (=ether glucuronide), which is quantitatively the most important metabolic pathway for diflunisal, is capacity-limited.…”

Section: Discussionmentioning

confidence: 99%

Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency.

Verbeeck¹,

Tjandramaga²,

Mullie³

et al. 1979

A single oral dose of 500 mg diflunisal was administered to control subjects and patients with varying degrees of renal insufficiency to estimate the disposition kinetics of this drug. 2 Diflunisal and the sum of its ester and ether glucuronides conjugates were measured fluorimetrically.3 In normals terminal plasma half-lives (Tip) of diflunisal and its glucuronides were very similar:10.8 h and 11.8 h respectively. The finding that plasma half-life was shortened with declining diflunisal plasma levels suggests capacity-limited elimination. 4 In subjects with normal renal function 78.6 + 2.7% of the administered dose was recovered in 72 h urine, mainly as the glucuronide conjugates. SWith increasing degree of renal function impairment Tip of diflunisal was progressively prolonged up to ten times normal probably due to slowed biotransformation. This was associated with increasing retention of the conjugated metabolites in plasma due to marked reduction of the urinary excretion of the glucuronide conjugates. 6 The apparent volume of distribution of diflunisal was very small in normals (7.3 ± 0.4 1) and was significantly increased in patients with renal insufficiency (up to 16.2 + 2.2 1). 7 Diflunisal elimination studies performed during haemodialysis did not reveal any significant change in diflunisal plasma half-time. In vivo ultrafiltration studies during haemodialysis have shown that diflunisal is 98-99% plasma protein bound in uraemic patients. 8 The present study indicates that although diflunisal is primarily eliminated by biotransformation,

“…Rates of urinary excretion of 4-hydroxydebrisoquine were tested for deviation from first-order kinetics by a statistical analysis based on the approach of Levy et al (1972). The observed urinary excretion rate of 4-hydroxydebrisoquine (V) and the calculated 'body load' of debrisoquine available for metabolism (DB;Cummings et al, 1967) The kinetic model employed assumes that metabolite elimination is very rapid in relation to the rate of metabolite formation, and the method of estimating ultimate recoveries of metabolites assumes that elimination is terminal and linear in the final period of the study; the use of ultimate recoveries of drug related material does, however, preclude the necessity of assuming quantitative absorption of the oral dose.…”

Section: Analysis Of Datamentioning

confidence: 99%

Genetically determined oxidation capacity and the disposition of debrisoquine.

Sloan¹,

Lancaster²,

Shah³

et al. 1983

1 The disposition in urine of debrisoquine and its hydroxylated metabolites has been studied in subjects of the 'extensive metabolizer' (EM; n = 5) and 'poor metabolizer' (PM; n = 5) phenotypes. The 4-hydroxylation of debrisoquine by PM subjects following a 10 mg oral dose was capacity-limited and displayed significant dose-dependency over a range of 1-20 mg. In contrast, the EM subjects' ability to perform this metabolic oxidation did not deviate from first-order kinetics over a dose range of 10-40 mg. 2 The disposition of debrisoquine in plasma following a 10 mg oral dose has been studied in EM (n = 4) and PM (n = 3) subjects. Whilst PM subjects displayed significantly higher plasma levels of debrisoquine at all time points following 1 h post-dosing, and higher values for areas under the plasma concentration-time curve (EM: 105.6 + 7.0 ng ml-' h; PM: 371.4 + 22.4 ng ml-' h, 2P < 0.0001), neither debrisoquine plasma half-life (EM: 3.0 + 0.5 h; PM: 3.3 + 0.4 h) nor renal clearance of the drug (EM: 152.8 + 30.3 ml min-'; PM: 137 + 4.5 ml min-') displayed significant inter-phenotype differences. 3 The results of these investigations show that the phenotyping of individuals for debrisoquine oxidation status by means of a 'metabolic ratio' derived from a single 0-8 h urine sample has a sound kinetic basis. The kinetic differences between the two phenotypes would strongly suggest that the metabolic defect manifested in PM subjects is one of pre-systemic elimination capacity.