New secondary metabolites of phenylbutyrate in humans and rats.
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 beta-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.
Kasumov
Takhar
T
Department of Nutrition, Room 280, Case Western Reserve University, 11000 Cedar Rd., Cleveland, OH 44106-7139, USA.
Brunengraber
Laura L
LL
Comte
Blandine
B
Puchowicz
Michelle A
MA
Jobbins
Kathryn
K
Thomas
Katherine
K
David
France
F
Kinman
Renee
R
Wehrli
Suzanne
S
Dahms
William
W
Kerr
Douglas
D
Nissim
Itzhak
I
Brunengraber
Henri
H
D000328:Adult; D000818:Animals; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D001711:Biotransformation; D003903:Deuterium; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010477:Perfusion; D010654:Phenylbutyrates / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013237:Stereoisomerism
D010654:Phenylbutyrates; D003903:Deuterium