Paracetamol tablets from different sources showed widely differing absorption patterns in man. As judged by a blood concentration at 45 min. of less than 10 pg./ml. whole blood, low absorption was usually found in 25 per cent of subjects. This may be reduced to less than 10 per cent by a new paracetamol/sorbitol tablet. This combination produced higher average blood levels at 45 min. than crushed tablets of paracetamol. There appears to be a relation between the absorption of the drug and both age and weight; this variation can be reduced by paracetamol/sorbitol.
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
Available methods are briefly surveyed and experiences with the Wänninen‐Ringbom and the Xylenol orange methods discussed. The latter is preferred for routine use.
The literature on the ethylenediaminetetra‐acetate method for determination of sulphate is reviewed and the limitations of the method are discussed. In the procedure now described, after precipitation of sulphate as barium sulphate, excess barium is precipitated with sodium lauryl sulphate and excess of the latter titrated with a suitable quaternary ammonium salt as described in Part I of this series.
A simple method is described for the routine determination of EDTA in pharmaceutical and I t depends on the addition of excess of ferric ions and determination of the similar preparations. excess spectrophotometrically with salicylic acid or thiocyanate.
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