Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome.

摘要: Gilbert's syndrome occurs in 5%-7% of the human population and is caused by an inherited deficiency glucuronidation endogenous bilirubin, resulting its accumulation jaundice. The authors present study have previously shown that rats with a similar bilirubin (Gunn rats) had reduced enhanced susceptibility to toxicity widely used analgesic, acetaminophen. Acetaminophen eliminated primarily glucuronidation, which prevents cytochrome P-450-catalysed bioactivation hepatotoxic reactive intermediate. purpose this was determine whether people Therefore, biotransformation acetaminophen, 20 mg/kg IV, investigated six subjects (total 41 +/- 6 mumol/L; mean SE) normal controls 11 2 P less than 0.01). Formation acetaminophen glucuronide conjugate measured high-performance liquid chromatography quantified ratio area under plasma concentration-time curve (AUC) from 0 hours for divided AUC molar percentage excreted urine during 24 as glutathione-derived conjugates (cysteine mercapturic acid). formation 31% lower (0.27 0.05 vs. 0.39 0.03; 0.05), 1.7-fold higher (3.5% 0.4% 2.1% 0.3%; 0.05). One control subject substantially decreased (0.20) (4.8%). Among all subjects, correlated inversely (r = -0.84; 0.001), indicating decrease major pathway elimination can shunt more drug through toxifying route. Thus, UDP-glucuronosyltransferase, evidenced jaundice, be paralleled other compounds. In these cases, jaundice phenotypic determinant bioactivation. On hand, some may acetaminophen; are not easily recognized.(ABSTRACT TRUNCATED AT 400 WORDS)