GLYCEROL PHENYLBUTYRATE
Clinical safety rating
cautionComprehensive clinical and safety monograph for GLYCEROL PHENYLBUTYRATE (GLYCEROL PHENYLBUTYRATE).
Glycerol phenylbutyrate is a prodrug that is metabolized to phenylacetate, which conjugates with glutamine to form phenylacetylglutamine. This compound is excreted by the kidneys, providing an alternative pathway for waste nitrogen excretion in patients with urea cycle disorders.
| Metabolism | Glycerol phenylbutyrate is metabolized by lipases to phenylbutyrate, which is then beta-oxidized to phenylacetate. Phenylacetate conjugates with glutamine via acyl-CoA synthetase and acyl-CoA:glutamine N-acyltransferase to form phenylacetylglutamine. |
| Excretion | Renal: >90% as phenylbutyrate metabolites (mainly phenylacetylglutamine) within 24 hours; fecal: <1% |
| Half-life | 0.8–1 hours (glycerol phenylbutyrate); 1.2–1.5 hours (phenylacetate); clinical context: short half-life requires thrice-daily dosing |
| Protein binding | 80–90% bound to albumin (phenylacetate and phenylbutyrate) |
| Volume of Distribution | 0.2–0.3 L/kg (phenylbutyrate and metabolites); clinical meaning: primarily distributes in extracellular fluid |
| Bioavailability | Oral: ~100% (prodrug is completely hydrolyzed to phenylbutyrate); intraperitoneal: not used clinically |
| Onset of Action | Oral: 2–4 hours to reduce plasma ammonia; intravenous not applicable |
| Duration of Action | 8–12 hours (ammonia-lowering effect); clinical notes: dosing every 8 hours maintains therapeutic effect |
| Molecular Weight | 342.43 |
450-600 mg/m2/day orally in three divided doses, rounded to the nearest 100 mg; maximum 20 g/day.
| Dosage form | LIQUID |
| Renal impairment | GFR 30-59 mL/min: reduce dose by 50%; GFR 15-29 mL/min: reduce dose by 75%; GFR <15 mL/min: contraindicated. |
| Liver impairment | Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce dose by 50%; Child-Pugh Class C: avoid use. |
| Pediatric use | 450-600 mg/m2/day orally in three divided doses; for children <20 kg, use 450 mg/m2/day; maximum 20 g/day. |
| Geriatric use | Start at low end of dosing range (450 mg/m2/day) and titrate based on renal function and tolerability; monitor for fluid overload. |
| 1st trimester | Limited human data; animal studies show no teratogenicity at clinically relevant doses. Use only if clearly needed. |
| 2nd trimester | Limited human data; no specific risks identified. Use only if benefit outweighs risk. |
| 3rd trimester | May be used; no known fetal harm. Monitor maternal ammonia levels. |
Clinical note
Comprehensive clinical and safety monograph for GLYCEROL PHENYLBUTYRATE (GLYCEROL PHENYLBUTYRATE).
| Placental transfer | Crosses placenta; extent unknown but likely low due to high protein binding. |
| Breastfeeding | Excreted into breast milk in low amounts; unlikely to cause adverse effects in infant. Consider risk-benefit. |
| Lactation Rating | L2 (Probably Compatible) |
| Teratogenic Risk | Glycerol phenylbutyrate is Pregnancy Category C. No adequate studies in pregnant women. In animal studies, no teratogenic effects at doses up to 2 times human exposure; however, fetal toxicity (reduced fetal weight, skeletal variations) occurred at maternally toxic doses. First trimester risk unknown; second and third trimesters: theoretical risk of maternal ammonia control affecting fetal development. |
| Fetal Monitoring | Monitor maternal plasma ammonia levels regularly; monitor liver function tests. Fetal monitoring: ultrasound for growth and anatomy. In third trimester, fetal surveillance for growth restriction. Monitor for maternal metabolic alkalosis. |
| Fertility Effects | No known effects on fertility in animal studies; no human data. Theoretical impact from hyperammonemia may affect reproductive function. |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to glycerol phenylbutyrate or any component
| Precautions | Monitor plasma ammonia levels, neurotoxicity (somnolence, lethargy, confusion) due to elevated phenylacetate; caution in hepatic or renal impairment; contains phenylalanine; avoid use with valproic acid; may cause hyperammonemia if dosing is incorrect; fluid and electrolyte imbalance; growth retardation in pediatric patients; pancreatic enzyme replacement may be needed. |
| Food/Dietary | Avoid high-protein meals without concurrent nitrogen-scavenging therapy; maintain a protein-restricted diet as prescribed. Do not mix the medication with acidic foods or drinks (e.g., orange juice, tomato juice) as it can cause precipitation. |
| Clinical Pearls | Monitor ammonia levels; glycerol phenylbutyrate is a prodrug that provides phenylbutyrate, which conjugates with glutamine to form phenylacetylglutamine, a nitrogen-scavenging agent excreted in urine. Dosing is weight-based (typically 5-12 mL/m²/day in divided doses) and must be adjusted with hepatic or renal impairment. Avoid use with probenecid as it reduces renal excretion of phenylacetylglutamine. Watch for hypernatremia and metabolic acidosis due to sodium content. |
| Patient Advice | Take with food or formula to reduce gastrointestinal side effects. · Measure dose using the provided oral syringe for accuracy. · Do not mix with acidic beverages (e.g., fruit juice) as it may precipitate. · Contact physician immediately if vomiting occurs within 20 minutes of dosing. · Maintain adequate hydration to ensure urinary excretion of waste nitrogen. · Store at room temperature, do not freeze. |
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