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

Abstract

1 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.

2 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 (P > 0.1; paired t-test).

3 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 (P > 0.1; paired t-test).

4 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.

5 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.

6 The ratios of the cumulative amounts of metabolites excreted in 24 h, were essentially the same as those measured in the 52 h samples.