Studies on the different metabolic pathways of antipyrine in man. I. Oral administration of 250, 500 and 1000 mg to healthy volunteers.

The plasma elimination rate of antipyrine, as measured by the salivary concentration decay, and the urinary excretion of antipyrine and its primary metabolites 4-hydroxy-antipyrine, norantipyrine, 3-hydroxymethyl-antipyrine and 3-carboxy-antipyrine was studied in five healthy volunteers, who received 250, 500 and 1000 mg antipyrine orally in a cross-over design. The mean antipyrine half-life and metabolic clearance were 11.5 ± 2.5 h (range 10.2-16.9 h) and 3.4 ± 0.9 l/h (range 1.7-4.2 l/h) respectively after 500 mg. These values were not significantly different after 250 or 1000 mg ( > 0.1; paired -test). In 52 h urine 3.3 ± 1.2% of the dose of 500 mg antipyrine was excreted unchanged as antipyrine, 28.5 ± 2.2% as 4-hydroxy-antipyrine, 16.5 ± 6.0% as norantipyrine, 35.1 ± 7.2% as 3-hydroxymethyl-antipyrine and 3.3 ± 0.8% as 3-carboxy-antipyrine. The values obtained at the other dose levels were not significantly different ( > 0.1; paired -test). At all dose levels 4-hydroxy-antipyrine and norantipyrine were excreted in urine entirely as glucuronides. After 500 mg antipyrine, 3-hydroxymethyl-antipyrine was excreted as glucuronide to the extent of 58 ± 9% of the total excreted amount. This percentage was not significantly different at the other dose levels. 3-Carboxy-antipyrine was excreted in the free form at all three dose levels. From 12 h of drug intake onwards, the urinary excretion rate curves of antipyrine and all its metabolites declined mono-exponentially with about the same half-life as the parent compound in saliva. The half-lives calculated from the excretion rate curves of 4-hydroxy-antipyrine, norantipyrine and 3-hydroxymethyl-antipyrine correlated significantly with the half-life of antipyrine in plasma. At all dose levels a relative delay in urinary excretion of 3-hydroxymethyl-antipyrine was observed compared to the urinary excretion of antipyrine and the other metabolites. The ratios of the cumulative amounts of metabolites excreted in 24 h, were essentially the same as those measured in the 52 h samples.