The Biotransformation of Phenylbutazone (Butazolidin ®)

Abstract

In the present paper a review of published work on the metabolic fate of phenylbutazone is given, inclusive of results from very recent radiotracer studies in man. Phenylbutazone, l,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine, being a highly lipophilic compound, is readily absorbed following oral administration to man, and is re-eliminated mostly in metabolized form via urine and faeces. In the biotransformation of phenylbutazone in the human organism two major pathways are involved, i.e. straightforward C-glucuronidation at the 4-position of the pyrazolidine ring and, to a much lesser extent, hydroxylation at one of the phenyl rings or at the n-butyl side chain. Hydrolytic cleavage of the amide bonds in the dioxopyrazolidine ring which, theoretically, would be a possible third pathway of biotransformation, does not take place to any significant extent. In contrast to man, the animal species studied, namely rat and dog, metabolize phenylbutazone predominantly through hydroxylation. This principal difference in metabolic handling may explain why the elimination rate of the drug from plasma is largely different in these species, the average half-lives being 3—4 hours in rat and dog as compared to about 80 hours in man following single doses. The enzyme systems that are primarily involved in phenylbutazone metabolism are mono-oxygenases in the animal species considered, and glucuronyltransferase in man. Auto-induction of enzymes, resulting in an enhanced elimination of the drug from plasma in the course of repeated administration, has unequivocally been proven for rat and dog only but not for man.