Can the toxic dose of paracetamol, 140 to 150 mg per kilo, be regarded as too high in obese people

Fråga: Can the toxic dose of paracetamol, 140 to 150 mg per kilo, be regarded as too high in obese people compared to normal weight people?

Sammanfattning: Based on two published studies on paracetamol pharmacokinetics in obese subjects and normal controls and the principles of allometric scaling or dosing according to body surface area, a toxic dose per kg bodyweight in normal weight subjects has to be adjusted to be comparable in morbidly obese patients. Allometric scaling using the commonly accepted exponent of 0.75 would imply a dose reduction by 8, 13 and 23 per cent respectivly (150 mg/kg versus 137, 123 and 115 mg/kg respectively) in patients weighing 100, 150 and 200 kg respectively) to obtain an equally toxic dose of paracetamol.

Svar: A search on Medline has revealed two original papers concerning phamacokinetics in obese subjects exposed to paracetamol (1,2). In the first study (1) four obese subjects (weights 133-189 kg, mean weight 154.5 kg) were compared with three volunteers of normal body weight after 650 mg paracetamol was administered orally. The elimination half-life was essentially the same in the obese patients and normal subjects. The maximum plasma concentrations were reached at a significantly later time and were significantly lower in the obese as compared to the normals. AUC per kg body weight was 0.13 in the obese subjects and 0.23 per kg ideal body weight. The normal subjects had an AUC per body weight of 0.38. As a fixed dose was given, the obese patients had about half the dose adjusted to body weight compared to the normal controls. We find this paper partly contradictory but, the authors conclude that "dosing according to total rather than ideal weight could lead to toxic or lethal effects...".

In the second study in 21 obese (14 women; seven men) and 21 controls (11 women; tenmen) were given 650 mg iv doses of paracetamol (2). Mean total body weights for the groups were as follows: obese men 134.9 kg, control men 70.6 kg, obese women 87.9 kg and normal woman 55.0 kg. The elimination half-life did not differ between subject groups, but volume of distribution was greater in obese than in control men (41 per cent) and greater in obese than control women (19 per cent). This means that a plasma concentration estimated at some time after the intake of a toxic paracetamol dose will underestimate the body load of paracetamol compared to the situation in a normal body weight patient.

The obese subjects had a clearance of 484 ml/min which gave a clearance per total body weight of 3.74 ml/min/kg and a clearance per ideal body weight can be calculated to 6.63 ml/min/kg. The corresponding numbers for the non obese controls were 323 ml/min, 4.55 ml/min/kg and 4.31 ml/min/kg respectively. This means that certainly, the metabolic clearance is higher in obese individuals but if a dose is scaled in proportion to total weight (135 kg) instead of ideal body weight (73 kg) (135/73 = 1.8) the obese patients will have a relatively higher dose than allowed for by their respective differences in clearance per kg ideal body weight (6.63/4.31 = 1.54).

The question how one should allow for different body size has recently been commented on by Holford (3). He concludes that there is most support for the so called allometric power model: y = axWxxb in which the exponent takes the value of 0.75. This principle for allowing for body size coincides approximately with the calculated body surface area within 1-100 kg of body weight. At higher body weights the allometric expression predicts a higher clearance than the surface area expression by Du Bois and Du Bois (4). If a certain dose level, eg 150 mg/kg is considered to be toxic for a 70 kg bw person allometric scaling (exponent 0.75) to body weights 100, 150 and 200 kg implies that the dose is oversized by 8, 13 and 23 per cent, respectively. Surface area allowance standardised to a 70 kg 180 cm individual would give for the same series of body weights, dose estimates to be oversized 23, 53 and 82 per cent, respectively. 1 Lee WH, Kramer WG, Granville GE: The effect of obesity on acetaminophen pharmacokinetics in man. J Clin Pharmacol 1981; 21: 284-287 (enclosed) 2 Abernathy DR, Divoll M, Greenblatt DJ, Ameer B: Obesity, sex, and acetaminophen disposition. Clin Pharmacol Ther 1982; 31: 783-790 (enclosed) 3 Holford NHG: A size standard for pharmacokinetics. Clin Pharmacokinet 1996; 30: 329-332 (enclosed) 4 DuBois D, DuBois EF: Clinical calorimetry. Tenth paper. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916; 17: 863