PT  - JOURNAL ARTICLE
AU  - Kasumov, Takhar
AU  - Brunengraber, Laura L.
AU  - Comte, Blandine
AU  - Puchowicz, Michelle A.
AU  - Jobbins, Kathryn
AU  - Thomas, Katherine
AU  - David, France
AU  - Kinman, Renee
AU  - Wehrli, Suzanne
AU  - Dahms, William
AU  - Kerr, Douglas
AU  - Nissim, Itzhak
AU  - Brunengraber, Henri
TI  - NEW SECONDARY METABOLITES OF PHENYLBUTYRATE IN HUMANS AND RATS
AID  - 10.1124/dmd.32.1.10
DP  - 2004 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 10--19
VI  - 32
IP  - 1
4099  - http://dmd.aspetjournals.org/content/32/1/10.short
4100  - http://dmd.aspetjournals.org/content/32/1/10.full
SO  - Drug Metab Dispos2004 Jan 01; 32
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