Simultaneous Modelling of the Michaelis‐menten Kinetics of Paracetamol Sulphation and Glucuronidation

SUMMARY The aim of the present study was to perform anin vivoestimation of the Michaelis‐Menten constants of the major metabolic pathways of paracetamol (APAP). A two‐occasion, single‐dose cross‐over trial was performed using 60 and 90 mg/kg doses of APAP in healthy patients undergoing third molar dental extraction. Plasma samples were collected over 24 h and urine was collected for 8 h after dosing. Twenty patients were enrolled in the study and complete data for plasma and urine were available for both doses for 13 volunteers who were included in the analysis; seven of the volunteers were men, the median age (range) was 22 years (19–31) and the median weight (range) was 68 kg (50–86). The mean (95% CI) kmfor APAP glucuronidation was 6.89 mmol/L (3.57–10.22) and the Vmaxwas 0.97 mmol/h per kg (0.65–1.28). The kmfor APAP sulphation was 0.097 mmol/L (0.041–0.152) and the Vmaxwas 0.011 mmol/h per kg (0.009–0.013). For the combined excretion of APAP‐cysteine and APAP‐mercapturate, the kmwas 0.303 mmol/L (0.131–0.475) and the Vmaxwas 0.004 mmol/h per kg (0.002–0.005). The estimates forin vivoMichaelis‐Menten constants for APAP glucuronidation and sulphation were in the order of those reported previously usingin vitromethods.