Drug information of Glycerol Phenylbutyrate

Decreases elevated plasma ammonia glutamine levels

Pre-prodrug that is metabolized by ester hydrolysis and pancreatic lipases to phenylbutyrate (PBA) and then by beta oxidation to phenylacetate (PAA); glutamine is conjugated with phenylacetate to form phenylacetylglutamine (PAGN), a nitrogen waste product that is excreted renally

The phenylacetylglutamine conjugate provides an alternate vehicle to urea for waste nitrogen excretion; for each gram of sodium phenylbutyrate administered, it is estimated that between 0.12–0.15 grams of phenylacetylglutamine nitrogen are produced

Peak plasma time: 2 hr (PBA), 4 hr (PAA), 4 hr (PAGN)

Peak plasma concentration: 37 mcg/mL (PBA), 14.9 mcg/mL (PAA), 30.2 mcg/mL (PAGN)

Protein Bound: 80.6-98% (PBA), 37.1-65.6% (PAA), 7-12% (PAGN)

Glycerol phenylbutyrate metabolized by hydrolyzed by pancreatic lipases and release phenylbutyric acid (PBA); PBA undergoes beta-oxidation to phenylacetic acid (PAA)

PAA is conjugated with glutamine in the liver and kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN

Excretion: 66.4-68.9% in urine as PAGN

Urea Cycle Disorders

Administer PO in 3 equally divided dosages, each rounded up to nearest 0.5 mL

Not to exceed 17.5 mL/day

Switching from sodium phenylbutyrate to glycerol phenylbutyrate

Total daily dose (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86

Total daily dose (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81

Phenylbutyrate-naïve

4.5-11.2 mL/m²/day (5-12.4 g/m²/day)

PEDIATRIC

<2 years: Give PO in 3 or more equally divided dosages, each rounded up to nearest 0.1 mL

≥2 years: Give PO in 3 equally divided dosages, each rounded up to nearest 0.5 mL

Hypersensitivity to phenylbutyrate (eg, wheezing, dyspnea, coughing, hypotension, flushing, nausea, rash)

Diarrhea

Flatulence

Headache

Children(Neutropenia-Vomiting-Constipation-Diarrhea-Pyrexia-Hypophagia-Cough, nasal congestion-Rhinorrhea-Rash-Papule-Gastroesophageal reflux-Increased hepatic enzymes-Feeding disorder (decreased appetite, hypophagia)-Anemia-Cough-Dehydration-Metabolic acidosis-Thrombocytosis-Thrombocytopenia-Lymphocytosis-Flatulence-Lethargy-Irritability/agitation)

Abdominal pain

Vomiting

Decreased appetite

Fatigue

Ammonia increased

Dyspepsia

Nausea

Abnormal body odor, including from skin, hair, and urine

Retching and gagging

Dysgeusia or burning sensation in mouth

Neutropenia

Pyrexia

Hypophagia

Cough

Nasal congestion

Rhinorrhea

Rash and papule

Safety and efficacy not established for N-acetylglutamate synthase (NAGS) deficiency

Increased exposure to phenylacetate (PAA), the major metabolite, associated with neurotoxicity

Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion/absorption of glycerol phenylbutyrate

Determine starting dose by patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence

~47% of dietary nitrogen is excreted as waste and ~70% of phenylbutyrate dose is converted to urinary phenylacetylglutamine (U-PAGN), so an initial estimated dose is 0.6 mL/g dietary protein ingested per day

Monitor plasma ammonia levels

Must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements)

 C

Based on animal data, this drug may cause fetal harm. There are no controlled data in human pregnancy