The Metabolism of Phenylbutazone in the Rat

Abstract

1. After administration of [¹⁴C]phenylbutazone by stomach tube to rats 1/3 of the radioactivity was excreted in the faeces and almost 2/3 in the urine over 48 h. Biliary excretion after intraperitoneal injection was slightly more than 1/3 of the dose in 24 h.

2. Major urinary metabolites were the side-chain oxidized metabolite II and a novel metabolite, III, which is oxidized both in a phenyl group and in the butyl side-chain. Only small amounts of oxyphenbutazone, unchanged phenyl-butazone and conjugates were found in the urine.

3. Analysis of bile and plasma and experiments with an isolated perfused rat liver indicate that oxyphenbutazone is also an important metabolite. This compound is further metabolized to metabolite III which, like oxyphenbutazone, can be conjugated with glucuronic acid before excretion.

4. The concentration of the highly protein-bound oxyphenbutazone exceeded that of the more readily formed metabolite II in the plasma of the intact animal 6 h after giving phenylbutazone.

5. It is concluded that phenylbutazone is extensively metabolized by oxidation in the rat. The γ-carbon in the butyl side-chain is the preferred site of oxidation, followed by the para position in one of the phenyl groups. Pharmacokinetic factors such as differences in the degree of protein binding favour the renal excretion of the side-chain oxidized metabolites.