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SIMULTANEOUS MODELLING OF THE MICHAELIS‐MENTEN KINETICS OF PARACETAMOL SULPHATION AND GLUCURONIDATION
Author(s) -
Reith David,
Medlicott Natalie J,
Kumara De Silva Rohana,
Yang Lin,
Hickling Jeremy,
Zacharias Mathew
Publication year - 2009
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2008.05029.x
Subject(s) - glucuronidation , sulfation , michaelis–menten kinetics , chemistry , urine , in vivo , acetaminophen , pharmacology , medicine , in vitro , biochemistry , enzyme , enzyme assay , microsome , biology , microbiology and biotechnology
SUMMARY1 The aim of the present study was to perform an in vivo estimation of the Michaelis‐Menten constants of the major metabolic pathways of paracetamol (APAP). 2 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). 3 The mean (95% CI) k m for APAP glucuronidation was 6.89 mmol/L (3.57–10.22) and the V max was 0.97 mmol/h per kg (0.65–1.28). The k m for APAP sulphation was 0.097 mmol/L (0.041–0.152) and the V max was 0.011 mmol/h per kg (0.009–0.013). For the combined excretion of APAP‐cysteine and APAP‐mercapturate, the k m was 0.303 mmol/L (0.131–0.475) and the V max was 0.004 mmol/h per kg (0.002–0.005). 4 The estimates for in vivo Michaelis‐Menten constants for APAP glucuronidation and sulphation were in the order of those reported previously using in vitro methods.