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Title: The disposition of paracetamol N-acetyl-D-L-methionate in healthy subjects and renally impaired patients
Author: Speirs, Graham C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1990
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Methionine is a glutathionc precursor which is effective in preventing liver damage after paracetamol overdosage. Paracetamol and N-acetyl-D-L-methioninc have been linked to form the paracetamol N-acetyl-D-L-methionate ester in an attempt to make a safer form of paracetamol. The disposition of paracetamol N-acetyl-D-L-methionate was studied in healthy subjects and patients with chronic renal failure. Each study was conducted as a double blind crossover clinical trial where each volunteer received Ig of paracetamol as 1) paracetamol and 2) paracetamol N-acetyl-D-L-mcthionate (2.146g). Existing methods of measurement of paracetamol and its metabolites in plasma and urine were validated and used. A method using solid phase extraction and analysis by HPLC with U.V. detection was developed for measurement of paracetamol N-acetyl-D-L-methionate in plasma. Using these methods, paracetamol N-acctyl-D-L-methionate hydrolysis was shown to be accelerated as pH and temperature increased. The rate of hydrolysis in plasma and whole blood at 37°C was rapid. Following administration of paracetamol to healthy subjects paracetamol was rapidly absorbed, distributed and extensively metabolised. This group provided control data consistent with other published reports. Following administration of paracetamol N-acetyl-D-L-methionate to healthy subjects the parent compound was rapidly hydrolysed by ubiquitous estcrases and the peak plasma paracetamol concentration was reduced and delayed. There was a corresponding delay in the appearance of paracetamol metabolites. Sulphate conjugation was significantly increased, however the relative bioavailability of paracetamol, the amount recovered in urine as glutathione derived conjugates and the elimination of paracetamol and its metabolites remained unaltered. Paracetamol absorption was essentially complete. Following administration of paracetamol to 7 non-dialysis and 5 haemodialysis patients with chronic renal failure, absorption of paracetamol was normal, however there was gross cumulation of metabolites and the late elimination phase of the parent compound was also impaired, the latter possibly occurring due to limited enterohepatic circulation of paracetamol metabolites with subsequent reabsorption of parent compound. In patients with chronic renal failure paracetamol metabolism was normal with the capacity for active tubular transport reduced to a greater extent than passive reabsorption. In the non-dialysis patients, the total 24 h urinary recovery of paracetamol was significantly reduced. Following administration of paracetamol H-acetyl-D-L-methionate to patients with chronic renal failure the appearance of paracetamol was delayed and the peak plasma paracetamol concentration reduced. All other phar-macokinetic variables obtained for paracetamol N-acetyl-D-L-methionate were, however, not significantly different from those obtained after administration of paracetamol alone to the same patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available