| Indication |
Glycerol phenylbutyrate is a nitrogen-binding agent for the chronic management of adult and pediatric patients >=2 years of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. |
| Mechanism of action |
The toxic accumulation of ammonia in the blood and brain arise from urea cycle disorders in which patients are deficient in critical enzymes or transporters that are involved in the synthesis of urea from ammonia. Glycerol phenylbutyrate is a prodrug - the major metabolite, phenylacetate (PAA) is the molecule that binds to nitrogen. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form phenylacetylglutamine (PAGN), which is excreted by the kidneys. PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion. |
| Absorption |
Glycerol phenylbutyrate is a prodrug in which phenylbutyrate (PBA) is released from the glycerol backbone by lipases in the gastrointestinal tract. PBA then undergoes beta-oxidtion to form PAA. When a single oral dose of 2.9 mL/m2 of Glycerol phenylbutyrate is given to fasting adult subjects, the pharmacokinetic parameters are as follows:
Tmax: PBA = 2 hours; PAA = 4 hours; PAGN = 4 hours.
Cmax: PBA = 37.0 ug/mL; PAA = 14.9 ug/mL; PAGN = 30.2 ug/mL.
In healthy subjects, the hydrolysis of glycerol phenylbutyrate is incomplete, but to what extent is unknown.
When glycerol phenylbutyrate is given to adult UCD patients, maximum plasma concentrations at steady state (Cmaxss) of PBA, PAA, and PAGN occurred at 8 h, 12 h, and 10 h, respectively, after the first dose in the day. Intact glycerol phenylbutyrate was not detectable in plasma in UCD patients.
|
| Protein binding |
PBA = 80.6% to 98.0%;
PAA = 37.1% to 65.6%;
PAGN = 7% to 12%. |
| Biotransformation |
Pancreatic lipases hydrolyze glycerol phenylbutyrate to release PBA from the glycerol backbone. PBA undergoes ?-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN. |
| Route of elimination |
Glycerol phenylbutyrate is mainly excreted as PAGN in the urine (68.9% in adults and 66.5% in pediatric UCD patients). PAA and PBA represented minor urinary metabolites, each accounting for <1% of the administered dose of PBA. |
| Toxicity |
Most common adverse reactions in >=10% of patients are diarrhea, flatulence, and headache. |
| Affected organisms |
|