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Title: Drug disposition in chronic renal failure : studies with paracetamol and frusemide
Author: Martin, Una
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1992
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Patients with renal failure react inappropriately to many drugs and have an increased incidence of side effects which may be due to changes in drug absorption, distribution, metabolism and excretion. Active or inactive polar drug metabolites which are normally excreted in the urine will accumulate and patients with end stage disease may depend completely on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD) for their elimination. Despite several single dose studies little information exists about the disposition of paracetamol and frusemide during chronic dosing in patients with renal failure including those maintained on dialysis and this has been investigated further in the present study. Six patients with end stage disease maintained on CAPD were given 1 g of oral paracetamol. Absorption was normal but plasma concentrations of the glucuronide and sulphate conjugates were greatly increased with little change during the observation period. The extraction capacity of the peritoneal membrane was low and the peritoneal clearance was < 7ml.min-1 for paracetamol and these conjugates. This disposition of paracetamol was then compared in 6 healthy volunteers and 6 conservatively managed patients with chronic renal failure taking 1 g 3 times a day for 10 days. Before dosing, the daily plasma concentrations of unchanged paracetamol were significantly higher in the patients (3.1 ± 0.6 versus 1.1 ± 0.3 mg.l-1) suggesting enterohepatic recycling with regeneration by hydrolysis of the conjugates and reabsorption of the parent compound. There was marked accumulation of the glucuronide conjugate (87.0 ± 69.0 versus 3.0 ± 0.5 mg.l-1 in the volunteers) which was dependent on the severity of the renal failure. The concentrations of the sulphate conjugate (25.0 ± 19.0 mg.l^-1) did not accumulate as predicted possibly due to depletion of inorganic sulphate. Patients with end stage renal failure maintained on haemodialysis were also treated with a similar regime of paracetamol. Neither the glucuronide nor sulphate conjugate reached the predicted mean plasma concentrations of 569 ± 150 and 434 ± 92 mg.l^-1 and extraction ratios of paracetamol and its conjugates were less than 50%.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available