The metabolism of phenolic antioxidants. 2. The metabolism of butylated hydroxyanisole in the rat

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Abstract
The metabolism of butylated hydroxyanisole and 2- and 3-tert.-butyl-4-hydroxyanisole in the rat is studied with particular emphasis on the fate of butylated hydroxyanisole at low doses. Increased urinary glucuronide and ethereal sulphate excretions during 5 days after dosing with 0.4 g of butylated hydroxyanisole/kg account for 61-82 and 11-16% respectively of the dose, and 5% of the dose is excreted, unchanged. For single oral doses of 0.002, 0.01, 0.025, 0.05 and 0.1 g of butylated hydroxyanisole/kg, overall recoveries of the dose from the urine were 81-100%. Glucuronide excretion accounts for 69-92% of the dose, and a slight increase in excretion of unchanged butylated hydroxyanisole occurs at the lowest doses. For single oral doses of 0.4 g of 2-tert.-butyl-4-hydroxyanisole 72% of the dose is excreted as ethereal sulphate in 5 days. With 3-tert.-butyl-4-hydroxyanisole 57-71% of the dose is excreted as glucuronide in 5 days. The administration of several successive daily doses of 0.5 g of butylated hydroxyanisole/kg, and of 3-tert.-butyl-4-hydroxyanisole, decreases the percentage recovery of conjugates and the proportion of ethereal sulphate excreted during dosing; repeated doses of 0.5 g of 2-tert.-butyl-4-hydroxy-anisoleAg cause a considerable increase in glucuronide and a decrease in ethereal sulphate conjugation of the dose. The isolation of the major metabolites, the probable formation of a demethylation product of 2-tert.-butyl-4-hydroxyanisole as a minor metabolite, the synthesis of the ethereal sulphates of both isomers and the synthesis of the glucuronamide of 2-tert.-butyl-4-hydroxyanisole are described.