Acetaminophen Metabolism

Acetaminophen (paracetamol) is extensively conjugated with glucuronic acid and sulfate before renal excretion. A minor metabolic route involves microsomal oxidation of acetaminophen to a hepatotoxic reactive intermediate, which subsequently undergoes glutathione (GSH) conjugation, yielding cysteine and mercapturate conjugates, both of which are excreted in the urine (Slattery et al., 1987). Evidence was presented by de Morais et al. (1989) that, in comparison with normal subjects, glucuronidation of acetaminophen is impaired in subjects with Gilbert syndrome (143500), a disorder in which glucuronidation of bilirubin is impaired. In studies of 125 Caucasian and 33 Oriental subjects, Patel et al. (1992) found no difference in the mean fraction of acetaminophen excreted as glucuronide: 51.5% in Caucasians versus 51.8% in Orientals. However, bimodality was apparent in both groups, with 20% of Caucasians and 33% of Oriental subjects displaying relatively extensive glucuronidation. In addition, glucuronidation displayed a strong negative correlation with sulfation (r = -0.97), suggesting a compensatory or complementary relationship between the 2 metabolic pathways. The mean fractional excretions of cysteine and mercapturate conjugates between Caucasians and Orientals did show significant differences (p = less than 0.005).