RT Journal Article SR Electronic T1 NEW SECONDARY METABOLITES OF PHENYLBUTYRATE IN HUMANS AND RATS JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 10 OP 19 DO 10.1124/dmd.32.1.10 VO 32 IS 1 A1 Takhar Kasumov A1 Laura L. Brunengraber A1 Blandine Comte A1 Michelle A. Puchowicz A1 Kathryn Jobbins A1 Katherine Thomas A1 France David A1 Renee Kinman A1 Suzanne Wehrli A1 William Dahms A1 Douglas Kerr A1 Itzhak Nissim A1 Henri Brunengraber YR 2004 UL http://dmd.aspetjournals.org/content/32/1/10.abstract AB Phenylbutyrate is used to treat inborn errors of ureagenesis, malignancies, cystic fibrosis, and thalassemia. High-dose phenylbutyrate therapy results in toxicity, the mechanism of which is unexplained. The known metabolites of phenylbutyrate are phenylacetate, phenylacetylglutamine, and phenylbutyrylglutamine. These are excreted in urine, accounting for a variable fraction of the dose. We identified new metabolites of phenylbutyrate in urine of normal humans and in perfused rat livers. These metabolites result from interference between the metabolism of phenylbutyrate and that of carbohydrates and lipids. The new metabolites fall into two categories, glucuronides and phenylbutyrate β-oxidation side products. Two questions are raised by these data. First, is the nitrogen-excreting potential of phenylbutyrate diminished by ingestion of carbohydrates or lipids? Second, does competition between the metabolism of phenylbutyrate, carbohydrates, and lipids alter the profile of phenylbutyrate metabolites? Finally, we synthesized glycerol esters of phenylbutyrate. These are partially bioavailable in rats and could be used to administer large doses of phenylbutyrate in a sodium-free, noncaustic form. The American Society for Pharmacology and Experimental Therapeutics