Determination of Blood and Other Tissue Concentrations of Paracetamol in Dog and Man

Abstract

The even distribution of non-conjugated paracetamol in the tissue waters of the dog has been confirmed. The mean tissue water: plasma water concentration is 1.1. A technique for the determination of non-conjugated paracetamol in man has been devised from existing methods. It has increased sensitivity and is applicable to the routine determination of a large number of samples. This method determines only non-conjugated paracetamol, the sulphated and glucuronated conjugates do not interfere with its accuracy, and it gives results comparable with previous methods. In man, 45 min. after oral administration of paracetamol, the whole blood : plasma concentration ratio is virtually constant at 1.1, indicating that the determination of non-conjugated paracetamol in whole blood should give a satisfactory indication of tissue level.THE only detailed study which appears to have been made on the distribution of paracetamol (N-acetyl-p-aminophenol) in tissues (Brodie and Axelrod, 1949) was done using one dog given phenacetin by mouth. Paracetamol levels were determined because these workers had previously shown it to be the major metabolite of phenacetin. Subsequently, Clark (1951) demonstrated that the metabolic pathways of paracetamol in man and the dog were similar. Because of the limited evidence available we have repeated the work of Brodie and Axelrod on the tissue distribution of paracetamol in the dog.The original analytical method of Brodie and Axelrod was used. A modification of this was subsequently used for the estimation of blood concentrations in man. EXPERIMENTAL METHODS Tissue Studies of Paracetamol in DogsFive dogs were given 300 mg./kg. paracetamol by mouth. After 2 hr. they were killed by intravenous pentobarbitone. The dose and time were chosen so that the tissue concentrations of the drug could be compared directly with those of Brodie and Axelrod (1949) for non-conjugated paracetamol values after administration of an equivalent dose of phenacetin.Determination of tissue levels was made by the method of Axelrod (1948, 1949), except that the pH for extraction was changed because it gave unsatisfactory results for liver homogenates. Tissues were homogenised in 0 . 1~ hydrochloric acid, and the homogenate neutralised and buffered at pH 6.6, before the extraction of non-conjugated paracetamol. By adding known amounts of the drug to tissues from treated animals, recovery was found to be 86 & 3 per cent from liver 440

Acute liver necrosis following overdose of paracetamol.

“…Levels were estimated as total p-aminophenol and were considerably in excess of those found with therapeutic dosage. The range of levels quoted by Gwilt et al (1963) is from 0.45 to 2.6 mg./100 ml. 45 minutes after the ingestion of 1 g. of paracetamol.…”

Liver Necrosis From Paracetamol

“…Barnes and Paget (1965) have reviewed evidence on the series of events leading to hepatic necrosis by drugs which accumulate in the liver. The fact that paracetamol in large but not lethal doses tends to accumulate in liver tissue water (Smith, 1958;Gwilt, Robertson & McChesney, 1963) might have indicated that liver necrosis should be looked for in animals given lethal doses. Actually what prompted us to look for liver necrosis was recent experience in this laboratory with liver necrosis produced by oral administration of tannic acid (Boyd, Bereczky & Godi, 1965).…”

Effect of hemodialysis on kinetics of acetaminophen elimination by anephric patients

“…§Results from two studies. plasma flow rate was used for this calculation because acetaminophen is equally distributed between erythrocytes and plasma 5 and is presumed to equilibrate rapidly between these two phases.…”