Glucuronide formation, phenobarbital

Both unmetabolized and parahydroxylated phenobarbital are excreted in the urine. The extent of glucuronide formation of phenobarbital varies widely. Phenobarbital elimination has first-order kinetics and thus is indepen-... 

An inspiring, and likely the first, example for the therapeutic application of enzyme induction to affect the metabolic fate of an endogenous substance has recently been reported by Yaffe and his associates (71) phenobarbital treatment has been used to prevent hyperbilirubinemia by inducing the glucuronyl transferase, enhanced glucuronide formation enabled increased bilirubin excretion and resulted in decreased serum bilirubin concentration. 

Type I Crigler-Najjar syndrome is a rare autosomal recessive disorder. It is characterized by severe congenital jaundice (serum bilirubin usually exceeds 20 mg/dL) due to mutations in the gene encoding bilirubin-UGT activity in hepatic tissues. The disease is often fatal within the first 15 months of life. Children with this condition have been treated with phototherapy, resulting in some reduction in plasma bilirubin levels. Phenobarbital has no effect on the formation of bilirubin glucuronides in patients with type I Crigler-Najjar syndrome. A liver transplant may be curative. 

Glucuronide synthesis is the rate-determining step in hepatic bilirubin metabolism. Drugs such as phenobarbital, for example, can induce both conjugate formation and the transport process. 

Pretreatment of mice with phenobarbital increases the activity of the enzyme that catalyzes the formation of the reactive metabolite and thus accelerates the depletion of hepatic glutathione ( ), but apparently does not affect the enzymes that catalyze the formation of the sulfate or the glucuronide conjugates because it does not alter the biological half-life of the drug in mice ( ). Thus, pretreatment of mice with phenobarbital increases the proportion of the dose of acetaminophen that becomes covalently bound to liver protein by increasing Ratio A and increases the incidence and severity of the liver necrosis ( >20). 

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