Formation of reactive metabolites of phenacetin in humans and rats

1. The metabolism of phenacetin to reactive intermediates in humans was estimated from the excretion of thio adducts in urine. N-Hydroxyphenacetin, a precursor of reactive metabolites, was also quantified.

2. Following an oral dose of phenacetin (10 mg/kg) to humans, these metabolites in 24 h urine were: paracetamol-3-cysteine, 4·4% dose; paracetamol-3-mercapturate, 3·9%; 3-thiomethylparacetamol, 0·4%; N-hydroxyphenacetin, 0·5%

3. Rats showed a considerable increase in N-hydroxyphenacetin excretion after chronic dosing with phenacetin at high dosage (500 mg/kg) for one month. Chronic dosing with a low dose (50 mg/kg) did not increase N-hydroxyphenacetin excretion, but a marked increase occurred on concomitant administration of aspirin and caffeine.