Phenylbutyric Acid: A Comprehensive Review of its Pharmacology, Therapeutic Applications, and Clinical Profile

1. Introduction to Phenylbutyric Acid

1.1. Overview and Significance

Phenylbutyric acid, a derivative of the short-chain fatty acid butyric acid, is a pharmacologically active compound with established and emerging therapeutic applications.[1] It is recognized as being naturally produced by the fermentation processes of colonic bacteria.[1] The primary clinical significance of phenylbutyric acid lies in its role as an adjunctive therapy for the chronic management of urea cycle disorders (UCDs), a group of rare genetic metabolic conditions characterized by the inability to effectively eliminate waste nitrogen.[1] Beyond this well-defined indication, phenylbutyric acid exhibits a broader spectrum of biological activities. These include functioning as a histone deacetylase (HDAC) inhibitor and as a chemical chaperone, properties that form the basis for its investigation in a variety of other pathological states.[1] The diverse pharmacological profile of phenylbutyric acid suggests its potential utility extends beyond its primary metabolic role, encompassing inflammatory conditions, certain malignancies, and neurodegenerative disorders.

1.2. Initial DrugBank and User-Provided Information

The compound under review is Phenylbutyric acid, identified in the DrugBank database with the accession number DB06819.[1] Its Chemical Abstracts Service (CAS) registry number is 1821-12-1.[2] Phenylbutyric acid is classified as a Small Molecule drug.[1]

Its principal approved use is as an adjunctive therapeutic agent for the chronic management of UCDs. This includes enzyme deficiencies presenting in the neonatal period (neonatal-onset deficiency) as well as those manifesting later in life (late-onset disease) in individuals with a prior history of hyperammonemic encephalopathy.[1]

Phenylbutyric acid is a fatty acid derivative that demonstrates a range of cellular and biological effects. Notably, it has been reported to possess anti-inflammatory properties and can act as a chemical chaperone, assisting in protein folding.[1] These characteristics have led to its application and investigation in the treatment of various genetic metabolic syndromes, neuropathies, in addition to UCDs.[1] The multifaceted nature of phenylbutyric acid, acting both as a crucial therapy for rare metabolic diseases and as a compound with broader biochemical activities, highlights its significance in pharmacology and medicine.

1.3. Scope of the Report

This report provides a comprehensive scientific review of phenylbutyric acid. It encompasses a detailed examination of its chemical and pharmaceutical characteristics, an in-depth analysis of its multiple mechanisms of action, and a thorough review of its pharmacokinetic and pharmacodynamic profiles. Furthermore, the report will cover its approved therapeutic indications, particularly in UCDs, as well as its investigational uses in other disease areas, supported by available clinical efficacy and safety data. Aspects such as dosage and administration, clinically relevant drug interactions, considerations for use in special patient populations, and an overview of its regulatory and market status will also be addressed. The information presented herein is synthesized from a range of scientific literature and drug information resources, primarily the provided research snippets.[1]

The dual nature of phenylbutyric acid—a well-established therapeutic for specific orphan diseases and an investigational agent with broader potential stemming from its fundamental biochemical properties—suggests a rich field for ongoing research and potential for drug repurposing.

2. Chemical and Pharmaceutical Profile

2.1. Chemical Identity and Properties

Phenylbutyric acid is chemically designated as 4-phenylbutanoic acid according to IUPAC nomenclature.[2]

• Synonyms: It is also known by several synonyms, including 4-PBA, PBA, benzenebutanoic acid, γ-phenylbutyric acid, and 4-phenyl-n-butyric acid.[2]
• Molecular Formula: The empirical chemical formula for phenylbutyric acid is C10​H12​O2​.[1]
• Molecular Weight: Its molecular weight is approximately 164.20 g/mol.[1]
• Physical Description: Phenylbutyric acid typically presents as a white or off-white crystalline powder or solid.[2]
• Solubility: It exhibits solubility in water, with reported values of 18 mg/mL [2] and 5.3 g/L at 40°C.[10] It is also soluble in chloroform and methanol.[2] The sodium salt, sodium phenylbutyrate, is freely soluble in methanol and practically insoluble in acetone and diethyl ether.[14]
• LogP: The octanol-water partition coefficient (LogP) is reported as 2.42, indicating moderate lipophilicity.[2]
• Melting Point: The melting point range is 47-51 °C.[2]
• Boiling Point: The boiling point is 290 °C at standard atmospheric pressure (760 mmHg).[2]

2.2. Pharmaceutical Formulations and Branded Products

Phenylbutyric acid is primarily available for therapeutic use as its sodium salt, sodium phenylbutyrate, and also as a glycerol ester prodrug, glycerol phenylbutyrate. Various branded and generic formulations have been developed to improve patient adherence and manage specific clinical needs.

• Sodium Phenylbutyrate Formulations:
• Buphenyl®: Marketed by Horizon Therapeutics US (previously by Ucyclyd Pharma/Medicis, with Amgen also linked as a marketer in some sources), Buphenyl is available as 500 mg tablets and as a powder for oral administration, which can also be given via nasogastric or gastrostomy tube.[1] The powder formulation is known for its strong salty taste.[14]
• Pheburane®: Marketed in the EU by Immedica Pharma AB and in the US by Medunik USA Inc. (formerly by other entities like Lucane Pharma and Orpharma Pty Ltd in Australia), Pheburane is a taste-masked formulation of sodium phenylbutyrate granules (483 mg sodium phenylbutyrate per gram of granules).[1] Each gram of Pheburane granules also contains 124 mg (5.4 mmol) of sodium and 768 mg of sucrose.[24]
• Olpruva™: Marketed by Acer Therapeutics, Olpruva provides sodium phenylbutyrate as pellets in packets for reconstitution into an oral suspension. It is available in various strengths (e.g., 2g, 3g) and also contains 124 mg of sodium per gram of sodium phenylbutyrate.[1]
• Ammonaps®: Marketed by Swedish Orphan Biovitrum AB, Ammonaps is considered the reference medicinal product for Pheburane in Europe.[4]
• Generic Sodium Phenylbutyrate: Generic versions of sodium phenylbutyrate tablets and powder are also available from various manufacturers, including Endo Operations, Sigmapharm Labs LLC, Alvogen, and Glenmark Pharmaceuticals Ltd.[17]
• Glycerol Phenylbutyrate Formulation:
• Ravicti®: Marketed by Horizon Therapeutics, Ravicti is an oral liquid formulation of glycerol phenylbutyrate. It is a pre-prodrug, specifically a triglyceride composed of three molecules of phenylbutyrate esterified to a glycerol backbone. Following oral administration, it is hydrolyzed in the gastrointestinal tract by pancreatic lipases to release phenylbutyrate.[8]

The development and availability of these varied formulations, including taste-masked granules and a liquid pre-prodrug, underscore a continuous effort within the pharmaceutical field to address the challenges associated with chronic administration of phenylbutyrate. These challenges primarily revolve around patient compliance, which can be affected by the unpalatable taste of earlier formulations, and the management of sodium intake, a critical consideration for certain patient populations. For instance, the strong salty taste of Buphenyl powder can be a significant barrier to adherence, particularly for pediatric patients who constitute a substantial portion of the UCD population.[14] Formulations like Pheburane and Olpruva attempt to mitigate this with taste-masking technologies.[4] Ravicti, as a tasteless and odorless liquid, offers another alternative to improve palatability and also importantly circumvents the high sodium load inherent to sodium phenylbutyrate preparations.[20] This latter feature is particularly beneficial for patients with comorbid conditions such as heart failure or renal impairment, where sodium restriction is crucial.[16]

Furthermore, the presence of generic sodium phenylbutyrate alongside these branded products introduces economic considerations into treatment decisions.[17] While newer formulations may offer advantages in tolerability or convenience, their higher cost often necessitates a clear medical justification for their use over less expensive generic options, especially in healthcare systems with formulary restrictions.[20] This complex interplay between clinical benefits, patient-specific needs, and pharmacoeconomic factors shapes the therapeutic landscape for phenylbutyrate.

3. Mechanisms of Action

Phenylbutyric acid exerts its therapeutic effects through multiple distinct molecular mechanisms, the relevance of which varies depending on the clinical context. Its primary, well-established mechanism involves nitrogen scavenging, crucial for its use in UCDs. Additionally, it functions as an HDAC inhibitor and a chemical chaperone, properties that account for its investigational use in a wider range of disorders.

3.1. Nitrogen Scavenging in Urea Cycle Disorders

The principal mechanism by which phenylbutyric acid benefits patients with UCDs is through an alternative pathway for waste nitrogen excretion.[1]

• Prodrug Activation: Phenylbutyrate, whether administered as sodium phenylbutyrate or glycerol phenylbutyrate, is a prodrug. It undergoes rapid metabolism, primarily through β-oxidation in the liver and kidneys, to its active metabolite, phenylacetate (PAA).[1]
• Conjugation with Glutamine: PAA subsequently conjugates with the amino acid glutamine via acetylation. This reaction, catalyzed by the enzyme phenylacetyl-CoA:L-glutamine-N-acetyltransferase, occurs predominantly in the liver and kidneys, forming phenylacetylglutamine (PAGN).[1] The formation of PAGN effectively "scavenges" glutamine, which serves as a major carrier of excess nitrogen in the body.
• Alternative Nitrogen Excretion: PAGN is a water-soluble compound that is readily excreted by the kidneys into the urine.[1] Each molecule of PAGN incorporates two nitrogen atoms (one from PAA's precursor and one from glutamine). This pathway provides an alternative route for the removal of waste nitrogen, effectively bypassing the defective enzymatic steps in the urea cycle.
• Therapeutic Effect: By facilitating the excretion of nitrogen as PAGN, phenylbutyric acid therapy leads to a reduction in elevated plasma concentrations of ammonia and glutamine, which are toxic at high levels, particularly to the central nervous system.[1]

The effective functioning of this nitrogen-scavenging pathway relies on the patient's intrinsic capacity for both the β-oxidation of phenylbutyrate to PAA and the subsequent enzymatic conjugation of PAA with glutamine. Conditions that might impair these metabolic steps, such as certain mitochondrial fatty acid oxidation disorders, severe liver disease affecting enzyme synthesis, or profound renal dysfunction impacting enzyme activity or glutamine homeostasis, could theoretically diminish the therapeutic efficacy of phenylbutyric acid in UCDs. Moreover, the availability of glutamine itself is a factor; while UCD patients often have elevated glutamine, severe catabolic states or inadequate protein intake could limit the substrate for PAGN synthesis.

The efficient renal excretion of PAGN is also critical. While PAA is the metabolite primarily associated with neurotoxicity, significant impairment in renal function could potentially lead to PAGN accumulation. The direct toxicological consequences of PAGN accumulation are not well-defined in the provided materials, but such accumulation could impose an additional metabolic burden or interfere with other renal functions, warranting consideration in patients with compromised kidney function.

3.2. Histone Deacetylase (HDAC) Inhibition

Phenylbutyric acid is also recognized for its activity as an inhibitor of histone deacetylases (HDACs).[2]

• Mechanism of HDAC Inhibition: HDACs are enzymes that remove acetyl groups from lysine residues on histone proteins. By inhibiting HDAC activity, phenylbutyric acid leads to an increase in histone acetylation (hyperacetylation). Acetylated histones are associated with a more open, transcriptionally active chromatin structure, thereby modulating the expression of various genes.[6]
• Therapeutic Relevance of HDAC Inhibition:
• Anticancer Effects: The anticancer properties of phenylbutyric acid are largely attributed to its HDAC inhibitory function. This can lead to cell cycle arrest, induction of apoptosis, and inhibition of cell proliferation, invasion, and migration in various cancer cell lines, including glioma, gastric cancer, breast cancer, and prostate cancer models.[2] For instance, in gastric cancer cells, 4-PBA was shown to inhibit HDAC activity, leading to increased histone H3 acetylation, particularly in the promoter region of the IL-8 gene. This resulted in IL-8 upregulation and subsequent activation of the Gab2/ERK signaling pathway, which had dose-dependent effects on cell behavior.[6]
• Fetal Hemoglobin (HbF) Induction: Phenylbutyric acid's ability to induce the production of fetal hemoglobin is a key mechanism underlying its investigational use in hemoglobinopathies such as sickle cell disease and β-thalassemia. This effect is thought to be mediated by the transcriptional activation of the γ-globin gene, a process influenced by histone acetylation status.[2]
• Other Modulatory Effects: Phenylbutyric acid may also influence cellular processes through its HDACi activity by affecting human Peroxisome Proliferator-Activated Receptor gamma (hPPARγ) activation and inhibiting protein isoprenylation.[2]

The HDAC inhibitory action of phenylbutyric acid is a broad-spectrum effect, influencing a multitude of gene expression programs. This pleiotropy can result in cellular outcomes that are highly dependent on the specific cellular context and the concentration of the drug. For example, studies in gastric cancer models have demonstrated that low concentrations of 4-PBA can promote cell migration via IL-8 upregulation (an effect linked to HDAC inhibition), whereas higher concentrations inhibit proliferation.[6] This dose-dependent duality and context specificity may contribute to the observed variability and often limited success of 4-PBA in clinical trials for solid tumors.[6] Establishing a consistent therapeutic window that selectively targets cancer cells without promoting undesirable effects in diverse tumor microenvironments remains a challenge.

It is important to recognize that the HDACi mechanism is pharmacologically distinct from the nitrogen-scavenging pathway relevant to UCDs. The concentrations of phenylbutyric acid required to achieve significant HDAC inhibition in target tissues (e.g., bone marrow for HbF induction, tumor microenvironment for anticancer effects) may differ from those achieved or necessary for effective ammonia reduction in UCD patients. This distinction is critical when considering the repurposing of phenylbutyric acid for non-UCD indications.

3.3. Chemical Chaperone Activity

Phenylbutyric acid also functions as a chemical chaperone, a property that involves assisting in the proper folding of proteins and thereby alleviating Endoplasmic Reticulum (ER) stress.[2]

• Mechanism of Chemical Chaperoning: ER stress occurs when unfolded or misfolded proteins accumulate within the ER lumen, overwhelming the cell's protein folding capacity and triggering the unfolded protein response (UPR). Chemical chaperones like phenylbutyric acid are thought to stabilize protein folding intermediates, prevent aggregation of misfolded proteins, or facilitate their correct conformational maturation.[8] By promoting proper protein folding, phenylbutyric acid can reduce the load of aberrant proteins in the ER and attenuate the UPR. While the precise molecular interactions are not fully elucidated for all target proteins, studies on Human Serum Albumin (HSA) indicate that 4-PBA can bind to fatty acid binding sites, inducing conformational changes and stabilizing the protein structure.[8] This general ability to interact with and stabilize proteins likely contributes to its chaperone effects within the ER. For example, 4-PBA has been reported to stabilize the expression of GRP78 (BiP), a key ER chaperone protein.[45]
• Therapeutic Relevance of Chemical Chaperone Activity:
• Cystic Fibrosis (CF): Phenylbutyric acid has been investigated for its potential to improve the cellular processing and trafficking of the mutated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, particularly the common ΔF508-CFTR variant, by aiding its folding and reducing its premature degradation.[47]
• Neurodegenerative and Neurological Disorders: Its chaperone activity is relevant to conditions where protein misfolding contributes to neuronal dysfunction and death. In a mouse model of GM2 gangliosidosis (Sandhoff disease), 4-PBA mitigated ER stress, reduced neuronal apoptosis, and led to improvements in motor function and lifespan.[45] In a viral-induced demyelination mouse model relevant to Multiple Sclerosis (MS), 4-PBA was shown to preserve the expression of Connexin 43 (Cx43), partly by upregulating its molecular chaperone ERp29, and also reduced viral infectivity.[42]
• Inflammatory Conditions: In a murine model of collagen-induced arthritis (a model for rheumatoid arthritis), 4-PBA attenuated disease severity. This effect was attributed to the inhibition of ER stress in synovial fibroblasts, which in turn suppressed their proliferation and production of inflammatory mediators via modulation of MAPK and NF-kB signaling pathways.[46]
• Myocardial Ischemia/Reperfusion (I/R) Injury: Pretreatment with 4-PBA protected cardiomyocytes from I/R-induced apoptosis by attenuating ER stress.[9]

The chemical chaperone effect of phenylbutyric acid is generally considered to be a result of relatively low-affinity, non-specific interactions that can stabilize a variety of proteins. This broad action can be advantageous, allowing it to potentially benefit diverse diseases characterized by protein misfolding and ER stress. However, the efficacy in specific conditions likely depends on achieving sufficient intracellular concentrations of phenylbutyric acid within the ER to exert a meaningful chaperone effect on the target protein(s). The binding of 4-PBA to plasma proteins like HSA [8] could modulate its free concentration and thus its availability to act as an intracellular chaperone, potentially influencing its distribution to target tissues and its overall efficacy in chaperone-dependent therapeutic applications.

The interplay between phenylbutyric acid's HDAC inhibitory and chemical chaperone activities is an area of interest. These two mechanisms are not mutually exclusive and could act synergistically in certain cellular contexts. For instance, HDAC inhibition might modulate the expression of endogenous chaperone proteins or components of the UPR pathway, thereby augmenting the cell's intrinsic capacity to cope with ER stress, while phenylbutyric acid concurrently provides direct chaperone assistance to misfolded proteins. The observation that 4-PBA can stabilize GRP78 expression [45] may be an example of such a cooperative effect, as GRP78 is a critical ER chaperone whose expression is often upregulated during ER stress.

4. Pharmacokinetics (PK)

The pharmacokinetic profile of phenylbutyrate has been characterized primarily from studies involving its sodium salt (sodium phenylbutyrate, NaPBA) and its glycerol ester prodrug (glycerol phenylbutyrate, GPB).

4.1. Absorption

Sodium phenylbutyrate is rapidly absorbed following oral administration, particularly under fasting conditions.[14]

• Tmax (Time to Peak Plasma Concentration) for Phenylbutyrate (PBA):
• For NaPBA formulations (tablets or powder), Tmax is typically observed within 1 to 1.35 hours after a single 5g dose.[14]
• For GPB (Ravicti®), which releases PBA more slowly due to hydrolysis of the glycerol ester, the Tmax for PBA is extended to approximately 2 hours.[4]
• Cmax (Peak Plasma Concentration) for Phenylbutyrate (PBA):
• Following a single 5g oral dose of NaPBA under fasting conditions, Cmax values for phenylbutyrate are in the range of 195 µg/mL (powder formulation) to 218 µg/mL (tablet formulation).[14]
• For GPB, a therapeutic dose yields a PBA Cmax of approximately 37 µg/mL, though the specific dose for this value is not detailed in the snippet.[32]
• Effect of Food:
• The effect of food on the absorption of NaPBA was initially described as unknown in older prescribing information.[14]
• More recent data and recommendations suggest that a high-fat, high-calorie meal can reduce the absorption of NaPBA. Consequently, it is often recommended to administer NaPBA before meals, particularly for individuals weighing less than 70 kg.[49]
• In contrast, specific formulations like Olpruva™ (NaPBA pellets) are recommended to be taken with food.[29] Similarly, Ravicti® (GPB liquid) is also advised to be administered with food or formula.[32] This variability underscores the importance of formulation-specific administration guidelines. The differing recommendations likely reflect efforts to optimize absorption profiles, manage gastrointestinal tolerance, or ensure consistent bioavailability across different product designs.

4.2. Distribution

• Volume of Distribution (Vd): The apparent volume of distribution for phenylbutyrate is reported to be 0.2 L/kg.[27]
• Protein Binding: Phenylbutyrate and its metabolites exhibit differential binding to plasma proteins:
• Phenylbutyrate (PBA): Highly protein-bound, in the range of 80.6% to 98%.[1]
• Phenylacetate (PAA): Moderately protein-bound, ranging from 37.1% to 65.6%.[4]
• Phenylacetylglutamine (PAGN): Exhibits low protein binding, approximately 7% to 12%.[4]
• An in vitro study indicated that when co-administered with tauroursodeoxycholic acid, the plasma protein binding of phenylbutyric acid is 82%.[1]

4.3. Metabolism

Phenylbutyrate is extensively metabolized, primarily in the liver and kidneys.[13]

• Prodrug Conversion: As a prodrug, phenylbutyrate is rapidly converted via β-oxidation to its principal active metabolite, phenylacetate (PAA).[1]
• Conjugation to PAGN: PAA is subsequently conjugated with glutamine. This reaction, catalyzed by the enzyme phenylacetyl-CoA:L-glutamine-N-acetyltransferase, forms phenylacetylglutamine (PAGN), which is the major metabolite destined for excretion.[1]
• Appearance of Metabolites: Following oral administration of NaPBA, measurable plasma levels of PAA are typically detected within 15 to 30 minutes, with PAGN appearing shortly thereafter.[14]
• Tmax of Metabolites: The Tmax for PAA is approximately 3.5 to 4 hours, and for PAGN, it is around 3.2 to 4 hours following NaPBA administration.[4]

4.4. Excretion

The primary route of elimination for phenylbutyrate metabolites is renal.

• Approximately 80-100% of an administered dose of phenylbutyrate is excreted by the kidneys as PAGN within 24 hours.[1]
• It is estimated that for each gram of sodium phenylbutyrate administered, between 0.12 and 0.15 grams of nitrogen are excreted in the form of PAGN.[1]

4.5. Half-life

The plasma elimination half-lives of phenylbutyrate and its major metabolites are relatively short:

• Phenylbutyrate (PBA): Approximately 0.76 to 0.8 hours.[14]
• Phenylacetate (PAA): Approximately 1.15 to 1.3 hours.[14]
• Phenylacetylglutamine (PAGN): Approximately 2.4 hours.[28]

4.6. Pharmacokinetics in Special Populations

• Gender: Significant gender-based differences in the pharmacokinetics of phenylbutyrate and PAA have been reported, with AUC and Cmax values being approximately 30-50% greater in females than in males. This difference is not observed for PAGN and may be attributable to the lipophilicity of sodium phenylbutyrate and consequent variations in volume of distribution.[13] While these pharmacokinetic differences are noted, current dosing guidelines generally do not differentiate based on gender. However, this factor could be relevant in instances of unexpected toxicity or suboptimal response, particularly at higher doses or in individuals with borderline metabolic capacity.
• Hepatic Insufficiency: Phenylbutyrate is metabolized in the liver. While some uncontrolled case studies in patients without UCDs but with impaired hepatic function suggested that metabolism and excretion were not affected, caution is strongly advised when administering the drug to patients with hepatic insufficiency.[13] In patients with impaired hepatic function, the conversion of PAA to PAGN may be slower, and some studies in cirrhotic patients have shown sustained and higher plasma levels of PAA.[27] Formulations like Olpruva™ recommend starting at the lower end of the dosing range for patients with hepatic impairment.[29]
• Renal Insufficiency: Since PAGN is primarily excreted by the kidneys, caution is necessary when administering phenylbutyrate to patients with renal insufficiency.[13] Furthermore, the sodium content of NaPBA formulations can be problematic in patients with severe renal insufficiency and fluid retention.[16]
• Pediatric Use: Pharmacokinetic studies for the original NaPBA formulations (e.g., Buphenyl®) were not specifically conducted in the primary pediatric population (neonates, infants, and children), with dosing often extrapolated from adult data or data from other formulations.[14] This represents a significant data gap, given that UCDs frequently manifest in this age group. The developing metabolic and renal functions in neonates and young infants may alter drug disposition and increase susceptibility to PAA neurotoxicity, necessitating careful dosing and vigilant monitoring.

The limited pharmacokinetic data in specific populations, such as young children and individuals with significant hepatic or renal impairment, underscores the necessity for cautious dose initiation, individualized titration based on clinical and biochemical monitoring (e.g., plasma ammonia, urinary PAGN), and heightened awareness for potential adverse effects.

Table 1: Key Pharmacokinetic Parameters of Phenylbutyrate and its Metabolites

Parameter	Phenylbutyrate (PBA)	Phenylacetate (PAA)	Phenylacetylglutamine (PAGN)	References
Tmax (oral)	~1-2 hours	~3.5-4 hours	~3.2-4 hours	4
Cmax (oral, 5g NaPBA)	~195-218 µg/mL	~45-49 µg/mL	~63-69 µg/mL	14
Half-life (t1/2​)	~0.76-0.8 hours	~1.15-1.3 hours	~2.4 hours	14
Volume of Distribution (Vd)	0.2 L/kg	Not explicitly stated	Not explicitly stated	27
Protein Binding	80.6-98%	37.1-65.6%	7-12%	1
Primary Elimination	Metabolism to PAA	Conjugation to PAGN	Renal excretion	1

Note: Values can vary based on formulation, patient population, and food intake.

5. Pharmacodynamics (PD)

5.1. Effects on Ammonia and Glutamine Levels in Urea Cycle Disorders

The primary pharmacodynamic effect of phenylbutyric acid in the context of UCDs is the reduction of elevated plasma ammonia and glutamine concentrations.[1] This is achieved by providing an alternative pathway for nitrogen excretion. As PAA conjugates with glutamine to form PAGN, it effectively removes two moles of nitrogen per mole of PAGN excreted, thereby lowering the systemic nitrogen burden that would otherwise contribute to hyperammonemia.[1]

5.2. Dose-Response Relationships

The dosing of phenylbutyrate in UCDs is individualized and guided by clinical and biochemical monitoring. The therapeutic goal is to maintain plasma ammonia levels within the normal range for the patient's age while ensuring adequate protein intake for growth and development.4

Urinary PAGN (U-PAGN) excretion has been identified as a clinically useful biomarker that correlates well with the administered dose of both NaPBA and GPB, aiding in dose selection and monitoring of therapeutic effect.31

It is important to note that the relationship between phenylbutyrate dose and nitrogen excretion may not be linear, particularly at higher doses. Studies suggest that the efficiency of PAA conjugation to PAGN may decrease at higher phenylbutyrate doses, potentially due to saturation of the enzymatic pathways involved.36 This implies an upper limit to the beneficial effect of dose escalation for ammonia scavenging. Exceeding this limit might not significantly improve nitrogen removal but could increase the risk of PAA accumulation and associated neurotoxicity. This observation underscores the importance of individualized dosing regimens and careful monitoring, rather than solely relying on escalating doses to manage hyperammonemia.

The pharmacodynamic effects related to HDAC inhibition or chemical chaperone activity are distinct from ammonia lowering. Assessing these effects in investigational settings would require different biomarkers, such as changes in histone acetylation, expression of target genes (e.g., γ-globin), reduction in ER stress markers, or functional restoration of specific misfolded proteins, depending on the condition being studied.

6. Therapeutic Indications

6.1. Approved Indications for Urea Cycle Disorders (UCDs)

Phenylbutyric acid, primarily in the form of its sodium salt (sodium phenylbutyrate) and glycerol ester prodrug (glycerol phenylbutyrate), is approved as an adjunctive therapy for the chronic management of patients with specific UCDs. These disorders are characterized by deficiencies in enzymes essential for the detoxification of ammonia into urea. The approved indications typically cover deficiencies of:

• Carbamylphosphate Synthetase (CPS) [1]
• Ornithine Transcarbamylase (OTC) [1]
• Argininosuccinic Acid Synthetase (AS) (also referred to as Argininosuccinate Synthetase or Citrullinemia Type 1) [1]

The therapy is indicated for:

• Neonatal-onset deficiency: Patients presenting with complete enzymatic deficiency within the first 28 days of life.[1]
• Late-onset disease: Patients presenting with partial enzymatic deficiency after the first month of life, who have a documented history of hyperammonemic encephalopathy.[1]

A critical component of management alongside phenylbutyrate therapy is strict adherence to a dietary protein restriction and, in some cases, supplementation with essential amino acids, arginine, and/or citrulline, as well as protein-free calorie supplements, to minimize exogenous nitrogen intake and support anabolism.[1]

6.2. Investigational and Other Reported Uses

The diverse mechanisms of action of phenylbutyric acid have prompted its investigation for a range of conditions beyond UCDs:

• Cystic Fibrosis (CF): Based on its chemical chaperone activity, phenylbutyric acid has been studied for its potential to improve the trafficking and function of the mutated CFTR protein (specifically the common ΔF508 variant) to the cell surface. It may also upregulate CFTR mRNA, possibly via its HDAC inhibitory effects.[47]
• Cancer: The HDAC inhibitory properties of phenylbutyric acid have been the primary rationale for its investigation as an antineoplastic agent. Preclinical studies have shown activity (e.g., growth arrest, apoptosis induction, inhibition of invasion/migration) in various cancer cell lines, including glioma, colon, gastric, breast, and prostate cancers.[2] However, clinical trial efficacy in solid tumors has generally been limited.[6]
• Hemoglobinopathies (Sickle Cell Disease, β-thalassemia): Phenylbutyric acid has been investigated for its ability to induce fetal hemoglobin (HbF) production. This effect is thought to be mediated by the transcriptional activation of the γ-globin gene, a consequence of HDAC inhibition.[2]
• Neurological Disorders and Neuroprotection:
• GM2 Gangliosidosis (Sandhoff Disease model): In preclinical models of this lysosomal storage disorder, 4-PBA has been shown to mitigate ER stress-induced neurodegeneration, improve motor function, and extend lifespan.[45]
• Multiple Sclerosis (MS model): In a viral-induced demyelination mouse model, 4-PBA demonstrated neuroprotective effects by preserving Connexin 43 expression (partly by upregulating its chaperone ERp29) and reducing viral infectivity.[42]
• The general neuroprotective potential is often attributed to its ability to reduce ER stress and act as a chemical chaperone.[2]
• Inflammatory Conditions:
• Phenylbutyric acid has demonstrated general anti-inflammatory effects.[1]
• Rheumatoid Arthritis (RA model): In a collagen-induced arthritis mouse model, 4-PBA attenuated disease severity by inhibiting ER stress, which in turn suppressed synovial fibroblast proliferation and their inflammatory responses.[46]
• Fetal Alcohol Spectrum Disorders (FASD model): Preclinical studies indicated that 4-PBA could alleviate ethanol-induced neuroapoptosis, glial activation, and ER stress in the developing brain.[52]

The broad range of investigational applications for phenylbutyric acid underscores its pleiotropic pharmacological effects. These effects stem from at least two distinct mechanisms—HDAC inhibition and chemical chaperoning—that are separate from its primary nitrogen-scavenging role in UCDs. This multi-mechanistic profile makes it an intriguing candidate for repurposing. However, while preclinical data for many of these investigational uses appear promising [42], the successful translation of these findings into robust clinical efficacy has been challenging, particularly in complex multifactorial diseases such as solid tumors.[6] The reasons for this translational gap are likely multifactorial, including pharmacokinetic challenges in achieving and maintaining therapeutic concentrations in specific target tissues, the complexity of the disease pathologies, and the potential for context-dependent or off-target effects.

7. Clinical Efficacy

7.1. Efficacy in Urea Cycle Disorders

The primary therapeutic goal in UCDs is the reduction of plasma ammonia levels to prevent acute hyperammonemic crises and mitigate long-term neurological sequelae.

• Ammonia and Glutamine Control: Phenylbutyrate formulations (both NaPBA and GPB) have demonstrated efficacy in decreasing elevated plasma ammonia and glutamine levels in patients with UCDs.[1] Comparative studies suggest that GPB is non-inferior to NaPBA regarding 24-hour ammonia control (assessed by NH3​−AUC0−24hr​). Some evidence indicates that GPB may offer more consistent or lower ammonia levels, potentially due to its slower release profile, which could lead to better overnight ammonia control.[31]
• Prevention of Hyperammonemic Crises (HACs): Long-term management with phenylbutyrate aims to reduce the frequency and severity of HACs. GPB has been shown to be successful in preventing HACs in the majority of UCD patients studied.[33]
• Survival Outcomes:
• Early diagnosis and initiation of comprehensive treatment, including phenylbutyrate and dietary management, are critical for survival, especially in neonatal-onset UCDs. Survival rates are reported to be around 80% for neonates diagnosed and treated within the first month of life. If diagnosed in utero and treatment is initiated before the onset of symptoms, survival rates can approach 100%.[21]
• For patients with late-onset UCDs who have experienced hyperammonemic encephalopathy, chronic therapy with sodium phenylbutyrate and dietary protein restriction is associated with high survival rates, reported as 98% [18] or greater than 90%.[21]
• Neurocognitive Outcomes:
• A significant challenge in UCD management is the prevention of irreversible neurological damage. Phenylbutyrate therapy does not reverse pre-existing neurological impairment, and some patients may experience ongoing neurologic deterioration despite treatment.[21] This underscores the critical importance of preventing hyperammonemic episodes, as high ammonia levels are directly linked to adverse neurological outcomes, coma, and death.[33]
• However, there is some encouraging evidence regarding neurocognitive benefits. Long-term treatment with GPB in pediatric UCD patients has been associated with improvements in executive functions, including behavioral regulation, goal setting, planning, and self-monitoring.[31] This suggests that consistent and potentially more stable ammonia control with formulations like GPB might contribute to better neurodevelopmental outcomes, although further research is needed to confirm these findings and understand the underlying mechanisms. Early diagnosis and effective long-term management of even mild UCDs are considered crucial for improving survival and preventing or minimizing neurocognitive impairment.[34]

The clinical utility of phenylbutyrate in UCDs is well-established for ammonia control and improving survival. However, the impact on neurocognitive outcomes remains a critical area of focus. While phenylbutyrate itself does not repair existing brain damage, its role in maintaining lower and more stable ammonia levels, as potentially offered by formulations like GPB with smoother pharmacokinetic profiles, may be crucial in protecting the developing brain and preserving cognitive function over the long term. The choice between NaPBA and GPB often involves balancing factors such as the extensive clinical experience and lower cost of NaPBA against the potential advantages of GPB in terms of taste, sodium load, and possibly more stable ammonia control.[20]

7.2. Efficacy in Investigational Uses

The clinical efficacy of phenylbutyric acid in its investigational applications is varied and generally less established than in UCDs.

• Cystic Fibrosis: A pilot study involving oral 4-PBA in ΔF508 CF patients demonstrated partial restoration of CFTR function in nasal epithelia.[48] While promising, this was a small, short-term study, and the authors noted the need for larger, longer-term trials with potentially more potent analogues.[48]
• Cancer: Despite encouraging preclinical data based on its HDAC inhibitory activity, the clinical efficacy of phenylbutyric acid in solid tumors has been limited in reported trials.[6] The complex, dose-dependent effects observed in vitro (e.g., pro-migratory at low concentrations vs. anti-proliferative at high concentrations in gastric cancer models [6]) may contribute to these challenges in achieving consistent therapeutic outcomes in human cancers.
• Hemoglobinopathies (Sickle Cell Disease, β-thalassemia): Phenylbutyric acid has been used in clinical trials with the aim of inducing fetal hemoglobin.[3] The provided snippets confirm its use in this context but do not detail specific efficacy outcomes from these trials.
• Other Conditions (Neurological, Inflammatory): For conditions like GM2 gangliosidosis, MS, and rheumatoid arthritis, the data supporting the use of phenylbutyric acid are primarily derived from preclinical animal models, as discussed in Section 6.2. Translation of these findings into human clinical efficacy requires further investigation.

8. Safety and Tolerability

The safety profile of phenylbutyric acid, primarily documented for its sodium salt and glycerol ester formulations, is generally manageable but requires careful monitoring for specific adverse events and adherence to precautions.

8.1. Common Adverse Events

Based on clinical trials and post-marketing experience with sodium phenylbutyrate formulations (e.g., Buphenyl®, Pheburane®), common adverse reactions (typically defined as occurring at an incidence of ≥3%) include [16]:

• Menstrual Dysfunction: Amenorrhea or irregular menstrual cycles (reported in 23% of menstruating patients in Buphenyl® trials).
• Decreased Appetite.
• Body Odor.
• Bad Taste or Taste Aversion.

For glycerol phenylbutyrate (Ravicti®), common adverse reactions (≥10%) in adults include diarrhea, flatulence, and headache.[32]

8.2. Serious Adverse Events and Warnings/Precautions

Several important warnings and precautions are associated with phenylbutyrate therapy:

• Neurotoxicity of Phenylacetate (PAA): PAA is the active metabolite of phenylbutyrate but can also be neurotoxic at elevated concentrations. Symptoms of PAA neurotoxicity may include somnolence, fatigue, lightheadedness, headache, dysgeusia (taste disturbance), hypoacusis (hearing impairment), disorientation, impaired memory, vomiting, and confusion. These effects are generally reversible upon discontinuation or dose reduction of phenylbutyrate. Monitoring for these symptoms is crucial, especially if plasma ammonia levels are normal or other intercurrent illnesses are absent. Plasma PAA levels may be measured if neurotoxicity is suspected.[15] Phenylacetate has also demonstrated neurotoxicity in rat pups.[25]
• Hypokalemia: The renal excretion of phenylacetylglutamine can lead to urinary loss of potassium, potentially causing hypokalemia. Serum potassium levels should be monitored regularly during therapy, and potassium supplementation initiated if necessary.[16]
• Sodium Retention and Edema (Sodium Phenylbutyrate Formulations): Sodium phenylbutyrate formulations (Buphenyl®, Pheburane®, Olpruva™) contain a significant amount of sodium (approximately 124 mg or 5.4 mmol of sodium per gram of sodium phenylbutyrate).[16] This sodium load can lead to fluid retention and edema, or exacerbate pre-existing conditions such as congestive heart failure, severe renal insufficiency, cirrhosis, or nephrosis. Careful calculation of total daily sodium intake from the medication is necessary, and the drug should be used with extreme caution, if at all, in patients with these conditions. If new-onset or worsening edema occurs, discontinuation or dose adjustment of the sodium-containing formulation and initiation of appropriate therapy for edema are recommended.[16] Glycerol phenylbutyrate (Ravicti®) does not contain sodium and may be a preferred alternative in patients requiring sodium restriction.[20]
• Gastrointestinal Disturbances: Less commonly, but potentially serious, gastrointestinal adverse events reported include abdominal pain, gastritis, nausea, vomiting, constipation, rectal bleeding, peptic ulcer disease, and pancreatitis.[16]
• Hematologic Abnormalities: Anemia, leukopenia, leukocytosis, thrombocytopenia, and thrombocytosis have been reported. Less common but serious hematologic events include aplastic anemia and ecchymoses.[16]
• Hepatic Effects: Elevations in liver enzymes (alkaline phosphatase, transaminases) and hyperbilirubinemia have been observed.[16]
• Metabolic Disturbances: Metabolic acidosis, alkalosis, hyperchloremia, hypophosphatemia, hyperuricemia, hyperphosphatemia, and hypoalbuminemia have been reported.[16]
• Considerations for Sucrose Content (Pheburane®, Olpruva™): Pheburane® contains 768 mg of sucrose per gram of sodium phenylbutyrate [24], and Olpruva™ also contains sucrose. This should be taken into account in patients with diabetes mellitus. These formulations should be avoided in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency.[25]

The risk of PAA neurotoxicity is a central safety concern. This risk is heightened if the metabolic conversion of PAA to PAGN is impaired (e.g., due to saturation of conjugation pathways at high phenylbutyrate doses [36]) or if renal excretion of PAGN is compromised, leading to PAA accumulation. This underscores the importance of individualized dosing, monitoring for neurological symptoms, and potentially measuring PAA levels if neurotoxicity is suspected, especially in vulnerable populations or those on high doses.

8.3. Contraindications

• Phenylbutyrate formulations are contraindicated in patients with known hypersensitivity to sodium phenylbutyrate, glycerol phenylbutyrate, or any component of the respective preparations.[16]
• Phenylbutyrate should not be used for the management of acute hyperammonemia, which is a medical emergency requiring immediate, more aggressive interventions to rapidly lower ammonia levels.[16]

8.4. Black Box Warnings

The provided prescribing information and summaries do not explicitly mention a "Black Box Warning" for phenylbutyric acid products in the way it is formally designated for some other medications. However, the seriousness of potential neurotoxicity from phenylacetate and the critical need to manage acute hyperammonemia as a medical emergency (for which phenylbutyrate is not indicated as a sole acute treatment) are consistently emphasized as significant warnings across product labels.[15] These warnings function with a similar gravity to black box warnings in highlighting life-threatening risks.

Table 2: Summary of Common and Serious Adverse Events Associated with Phenylbutyric Acid Therapy

System Organ Class	Common Adverse Events (Incidence ≥3% for NaPBA)	Serious / Clinically Significant Adverse Events (Less Common or Potentially Severe)	References
General/Metabolic	Decreased appetite, Body odor, Bad taste/taste aversion, Diarrhea (GPB), Flatulence (GPB), Headache (GPB)	Metabolic acidosis, Alkalosis, Hypokalemia, Hypernatremia (with NaPBA), Edema (with NaPBA), Hypophosphatemia, Hyperuricemia, Hypoalbuminemia	16
Nervous System	Headache (NaPBA)	Neurotoxicity of Phenylacetate: Somnolence, Fatigue, Lightheadedness, Disorientation, Memory impairment, Dysgeusia, Hypoacusis, Confusion, Vomiting (if neurotoxic)	15
Reproductive	Menstrual dysfunction (amenorrhea, irregular cycles)	-	16
Hematologic	-	Anemia, Leukopenia, Leukocytosis, Thrombocytopenia, Thrombocytosis, Aplastic anemia (rare), Ecchymosis	16
Gastrointestinal	Nausea, Vomiting, Constipation (less common with NaPBA)	Abdominal pain, Gastritis, Peptic ulcer, Rectal hemorrhage, Pancreatitis	16
Hepatic	-	Increased alkaline phosphatase, Increased transaminases, Hyperbilirubinemia	16
Cardiac	-	Arrhythmia (uncommon), Worsening of heart failure (due to sodium load with NaPBA)	16
Skin	-	Rash	24

GPB: Glycerol Phenylbutyrate (Ravicti®); NaPBA: Sodium Phenylbutyrate (e.g., Buphenyl®, Pheburane®, Olpruva™).

This table is not exhaustive; refer to full prescribing information for complete details.

9. Dosage, Administration, and Formulations

Effective management of UCDs with phenylbutyric acid requires careful attention to dosing, route of administration, and the specific characteristics of available formulations.

9.1. General Dosing Principles for Urea Cycle Disorders

• Adjunctive Therapy: Phenylbutyrate therapy is always adjunctive to rigorous dietary protein restriction and, in many cases, supplementation with essential amino acids (such as arginine or citrulline, depending on the specific enzyme deficiency) and protein-free calorie sources. This comprehensive approach aims to minimize endogenous nitrogen production while ensuring adequate nutrition for growth and development.[1]
• Individualized Dosing: The daily dose of phenylbutyrate must be individualized for each patient. Factors influencing dosage include the patient's age, body weight or body surface area (BSA), dietary protein tolerance, residual enzyme activity (if any), and plasma ammonia levels.[4]
• Divided Doses: The total calculated daily dose is typically divided into equal amounts and administered with each meal or feeding. This usually translates to three to six administrations per day, particularly in younger children who eat more frequently.[19]
• Monitoring: Regular monitoring of plasma ammonia levels, plasma amino acids, nutritional status, and clinical condition is essential to guide dose adjustments and ensure optimal therapeutic outcomes.[24] Urinary PAGN levels can also serve as a biomarker for assessing compliance and adequacy of dosing.[31]

9.2. Sodium Phenylbutyrate Dosing (e.g., Buphenyl®, Pheburane®, Olpruva™)

The recommended dosage for sodium phenylbutyrate is generally based on body weight for smaller children and BSA for larger children and adults:

• Neonates, Infants, and Children < 20 kg: The usual total daily dose ranges from 450 mg/kg/day to 600 mg/kg/day.[19]
• Children ≥ 20 kg, Adolescents, and Adults: The usual total daily dose ranges from 9.9 g/m²/day to 13.0 g/m²/day.[19]
• Maximum Daily Dose: The safety and efficacy of doses exceeding 20 grams per day have not been established, and this is generally considered the maximum daily dose.[19]

9.3. Glycerol Phenylbutyrate (Ravicti®) Dosing

Dosing for Ravicti® can be initiated in treatment-naïve patients or by converting from sodium phenylbutyrate.

• Conversion from Sodium Phenylbutyrate: Patients switching from NaPBA to GPB should receive a GPB dosage that provides an equivalent amount of phenylbutyric acid. The conversion factors are:
• Total daily dosage of Ravicti® (mL) = Total daily dosage of NaPBA tablets (g) x 0.86.[32]
• Total daily dosage of Ravicti® (mL) = Total daily dosage of NaPBA powder (g) x 0.81.[32]
• Naïve Patients (≥2 years of age): The recommended dosage range, based on BSA, is 4.5 mL/m²/day to 11.2 mL/m²/day (equivalent to 5 g/m²/day to 12.4 g/m²/day of PBA).[32] For patients with some residual enzyme activity not adequately controlled by diet alone, a starting dose of 4.5 mL/m²/day is recommended. An initial estimated dose can also be based on dietary protein intake (approximately 0.6 mL Ravicti® per gram of dietary protein ingested per 24 hours).[32]
• Maximum Daily Dose: The total daily dosage of Ravicti® should generally not exceed 17.5 mL.[38]

9.4. Administration

The method of administration varies by formulation:

• Sodium Phenylbutyrate Powder (e.g., Buphenyl®, Generic): Can be mixed with food (e.g., applesauce, mashed potatoes) or drink (e.g., water, fruit juices, protein-free infant formulas) immediately before administration. It can also be administered via nasogastric (NG) or gastrostomy (G) tubes.[14]
• Sodium Phenylbutyrate Tablets (e.g., Buphenyl®): For oral administration.[14]
• Pheburane® Granules (Sodium Phenylbutyrate): Taste-masked granules that can be sprinkled onto a spoonful of solid food or placed directly in the mouth and swallowed immediately with a drink. It is important that they are taken immediately after mixing to preserve the taste-masking.[4]
• Olpruva™ Pellets (Sodium Phenylbutyrate): The entire contents of the Olpruva™ packet(s) must be mixed with the contents of a Mix-Aid™ packet (provided with the medication) in approximately 4 ounces (120 mL) of water to form a suspension. This suspension should be stirred and consumed entirely within 5 minutes to minimize dissolution of the pellet coating. An additional 4 ounces of water should be used to rinse the cup and ensure all medication is consumed. Olpruva™ is for oral administration only and should not be administered via NG or G-tubes.[29]
• Ravicti® Liquid (Glycerol Phenylbutyrate): Administered directly into the mouth via an oral syringe. It should be taken with food or formula. For infants who are breastfeeding, Ravicti® should be administered just prior to breastfeeding. It can also be administered via NG or G-tubes.[32]

9.5. Comparison of Formulations

The choice of phenylbutyrate formulation is a critical aspect of UCD management, influenced by patient age, tolerability, specific clinical needs (e.g., sodium restriction), and practical considerations like administration route and cost.

Table 4: Comparison of Marketed Phenylbutyrate Formulations for Urea Cycle Disorders

Feature	Generic Sodium Phenylbutyrate	Buphenyl®	Pheburane®	Olpruva™	Ravicti®
Active Ingredient	Sodium Phenylbutyrate	Sodium Phenylbutyrate	Sodium Phenylbutyrate	Sodium Phenylbutyrate	Glycerol Phenylbutyrate (prodrug of Phenylbutyric Acid)
Formulation Type	Powder, Tablets	Powder, Tablets	Taste-masked Granules	Coated Pellets for Oral Suspension	Oral Liquid
Available Strengths/Concentrations	Varies by manufacturer (e.g., 3g/tsp powder, 500mg tablet)	3g/tsp powder, 500mg tablet	483 mg NaPBA/g granules	2g, 3g, 4g, 5g, 6g, 6.67g NaPBA per packet	1.1 g/mL PBA equivalent
Administration Notes	With meals/feedings; Powder can be mixed with food/drink or given via NG/G-tube	With meals/feedings; Powder can be mixed with food/drink or given via NG/G-tube	With meals/feedings; Sprinkle on food or swallow with drink immediately	With meals/feedings; Mix with Mix-Aid™ and water, consume within 5 min; Not for NG/G-tube	With food/formula; Administer via oral syringe; Can be given via NG/G-tube
Taste/Odor Profile	Strong salty taste, distinct odor	Strong salty taste, distinct odor	Taste-masked (sucrose-coated)	Taste-masked (coating designed to minimize taste until swallowed)	Tasteless/Odorless
Sodium Content per gram of PBA equivalent	High (approx. 124 mg sodium per gram NaPBA)	High (approx. 124 mg sodium per gram NaPBA)	High (approx. 124 mg sodium per gram NaPBA)	High (approx. 124 mg sodium per gram NaPBA)	Negligible (no sodium salt)
Key Advantages	Lower cost (generic)	Established use, multiple formulations	Improved palatability vs. standard NaPBA powder/tablets	Improved palatability, pre-measured packets	Tasteless/odorless, no sodium load, potentially smoother PK profile (slower release)
Key Disadvantages/ Considerations	Poor palatability, high sodium load	Poor palatability, high sodium load	Contains sucrose, high sodium load	Contains sucrose, high sodium load, not for tube feeding	Higher cost, requires hydrolysis to active PBA
References	14	1	1	1	8

This comparative overview illustrates that while all formulations aim to deliver phenylbutyric acid for nitrogen scavenging, they differ significantly in aspects that impact patient adherence and suitability for specific patient subgroups. The development from basic sodium phenylbutyrate powders and tablets to more sophisticated taste-masked granules and the glycerol ester prodrug reflects ongoing efforts to optimize therapy for this chronic, life-long condition. The choice of formulation must therefore be carefully individualized.

10. Drug Interactions

The metabolism and excretion of phenylbutyric acid and its metabolites can be influenced by concomitant medications, and phenylbutyrate itself may affect the disposition of other drugs.

• Probenecid: Probenecid is known to inhibit the renal tubular secretion of many organic compounds, including hippuric acid (a conjugate of benzoate, another nitrogen scavenger). It is therefore likely that probenecid may affect the renal excretion of PAGN, the primary conjugated metabolite of phenylbutyrate. Inhibition of PAGN excretion could potentially lead to accumulation of PAA, thereby increasing the risk of neurotoxicity.[16] This interaction is particularly relevant because impaired elimination of the nitrogen-carrying metabolite could reduce the overall efficacy of phenylbutyrate as a nitrogen scavenger, while simultaneously increasing exposure to the potentially toxic PAA.
• Corticosteroids: Systemic corticosteroids (e.g., prednisone, dexamethasone) can induce a catabolic state, leading to increased body protein breakdown. This, in turn, elevates plasma ammonia levels, potentially counteracting the therapeutic effect of phenylbutyrate in UCD patients.[16] Patients requiring concomitant corticosteroid therapy should be monitored closely for ammonia control.
• Valproic Acid and Haloperidol: There are published reports suggesting that valproic acid and haloperidol can induce hyperammonemia.[16] Co-administration of these drugs with phenylbutyrate in UCD patients should be approached with caution, and plasma ammonia levels should be carefully monitored.
• CYP450 Interactions (Glycerol Phenylbutyrate - Ravicti®): Glycerol phenylbutyrate has been shown to be a weak inducer of Cytochrome P450 3A4 (CYP3A4). Therefore, co-administration of Ravicti® with drugs that are substrates of CYP3A4 may lead to decreased systemic exposure and potentially reduced efficacy of these concomitant medications. Monitoring for decreased efficacy is recommended for CYP3A4 substrates, particularly those with a narrow therapeutic index, such as alfentanil, quinidine, cyclosporine, and midazolam.[32]
• Potential CYP Inhibition by Phenylbutyric Acid (General): Broader drug interaction databases, such as DrugBank, suggest that phenylbutyric acid itself may decrease the metabolism of drugs metabolized by various CYP enzymes, although the specific isoforms are not always detailed in the provided summaries.[1] Examples listed include tricyclic antidepressants (amitriptyline, amoxapine), amphetamine, aripiprazole, atenolol, and atomoxetine. This potential for broader CYP enzyme inhibition by phenylbutyric acid or its metabolites is a significant consideration that warrants further investigation, as UCD patients are often on multiple concomitant medications. If phenylbutyric acid indeed inhibits key drug-metabolizing enzymes, this could lead to clinically significant increases in the exposure and toxicity of co-administered drugs. This aspect is not as prominently featured in the product-specific prescribing information for UCDs, which tend to focus on the interactions mentioned above (probenecid, corticosteroids, etc.) or the CYP3A4 induction by GPB.

The potential for drug interactions necessitates a thorough review of all concomitant medications when initiating or adjusting phenylbutyrate therapy.

Table 3: Clinically Significant Drug Interactions with Phenylbutyric Acid

Interacting Drug/Class	Potential Mechanism of Interaction	Potential Clinical Consequence	Management Recommendation	References
Probenecid	Inhibition of renal tubular secretion of PAGN and PAA	Increased plasma PAA levels, potential neurotoxicity, decreased nitrogen excretion	Avoid concomitant use if possible; monitor PAA levels and for neurotoxicity if co-administered	16
Corticosteroids (systemic)	Increased protein catabolism	Increased plasma ammonia, counteraction of phenylbutyrate efficacy	Monitor ammonia levels closely; adjust phenylbutyrate dose if necessary	16
Valproic Acid, Haloperidol	Potential to induce hyperammonemia	Increased plasma ammonia	Use with caution; monitor ammonia levels closely	16
CYP3A4 Substrates (with Glycerol Phenylbutyrate)	Weak induction of CYP3A4 by GPB	Decreased systemic exposure and efficacy of CYP3A4 substrates	Monitor efficacy of co-administered CYP3A4 substrates, especially those with narrow therapeutic index	32
Various Drugs Metabolized by CYPs (potential with Phenylbutyric Acid)	Potential inhibition of various CYP enzymes by phenylbutyric acid/metabolites	Increased exposure and potential toxicity of co-administered drugs	Use with caution; monitor for adverse effects of concomitant medications. Consult comprehensive drug interaction resources.	1

This table is not exhaustive and focuses on interactions highlighted in the provided materials. Clinicians should consult comprehensive drug interaction resources.

11. Use in Special Populations

11.1. Pregnancy

• Sodium Phenylbutyrate: Animal reproduction studies have not been conducted with sodium phenylbutyrate, and it is not known whether it can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[16] The European Medicines Agency (EMA) SmPC for Pheburane® notes that its active metabolite, phenylacetate, produced lesions in cortical pyramidal cells of rat pups exposed in utero, and therefore, the use of Pheburane® is not recommended during pregnancy.[24] Women of childbearing potential should be advised to avoid becoming pregnant while on therapy.[23]
• The limited data and potential for fetal harm create a significant clinical dilemma for women with UCDs who require lifelong treatment and wish to become pregnant. This necessitates careful multidisciplinary counseling regarding the risks and benefits.

11.2. Lactation

• Sodium Phenylbutyrate: It is not known whether sodium phenylbutyrate or its metabolites are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, breastfeeding is generally not recommended during treatment with Buphenyl® or Pheburane®.[15]
• Glycerol Phenylbutyrate (Ravicti®): For infants who are breastfeeding, Ravicti® should be administered to the mother just prior to breastfeeding.[38] This specific recommendation for Ravicti® suggests a different approach or perceived risk profile compared to sodium phenylbutyrate, possibly due to differences in formulation or available data, though this is not explicitly clarified in the snippets.

11.3. Pediatric Use

Phenylbutyrate is indicated for use in pediatric patients with UCDs, including neonates with neonatal-onset deficiency and older children with late-onset disease.[1]

• Specific weight-based (for children < 20 kg) and BSA-based (for children ≥ 20 kg) dosing guidelines are provided for sodium phenylbutyrate formulations.[19]
• Glycerol phenylbutyrate (Ravicti®) was initially approved by the FDA for patients ≥2 years of age, as data were insufficient to provide safe and effective dosing instructions for patients <2 years, with concerns regarding PAA levels and potential neurotoxicity in this very young age group.[37] However, subsequent EMA information indicates its use across all pediatric ages [35], and current US labeling for Ravicti also includes patients younger than 2 years, with specific dosing recommendations.
• The developing metabolic pathways and renal function in neonates and young infants may alter the pharmacokinetics and pharmacodynamics of phenylbutyrate, potentially increasing their vulnerability to PAA neurotoxicity. Phenylacetate has been shown to cause neurotoxicity in rat pups.[25] Therefore, meticulous dose titration, vigilant clinical monitoring for signs of neurotoxicity, and regular biochemical monitoring (plasma ammonia, PAA if indicated) are particularly critical in this population.

11.4. Geriatric Use

Specific information on the use of phenylbutyrate for UCDs in geriatric patients is limited in the provided materials. While UCDs are typically diagnosed earlier in life, individuals with milder forms or heterozygous carriers may present or require ongoing management into older age. General principles of geriatric pharmacology would apply, including cautious dose selection due to the higher likelihood of decreased renal, hepatic, or cardiac function, and the presence of comorbidities and polypharmacy. The prescribing information for Pheburane® and Olpruva™ (derived from a general sodium phenylbutyrate monograph) suggests that appropriate studies have not demonstrated geriatric-specific problems that would limit their usefulness, but caution is advised due to potential age-related organ dysfunction.[30]

11.5. Renal Impairment

Since phenylacetylglutamine (PAGN), the primary excretory product of phenylbutyrate metabolism, is eliminated by the kidneys, caution is advised when administering phenylbutyrate to patients with renal impairment.[13] Impaired renal function could lead to accumulation of PAGN and potentially PAA, increasing the risk of toxicity. Additionally, for sodium phenylbutyrate formulations, the significant sodium load is a major concern in patients with severe renal insufficiency, as it can exacerbate fluid retention and edema.[16]

11.6. Hepatic Impairment

Phenylbutyrate is metabolized in the liver to PAA, and PAA is subsequently conjugated with glutamine in the liver (and kidneys).[13] Therefore, caution is warranted in patients with hepatic insufficiency. Impaired hepatic function may slow the conversion of PAA to PAGN, potentially leading to PAA accumulation and increased risk of neurotoxicity. Some studies in cirrhotic patients (without UCDs) showed sustained and higher plasma levels of PAA after sodium phenylbutyrate administration.[27] The prescribing information for Olpruva™ recommends starting at the lower end of the dosing range for patients with hepatic impairment and maintaining them on the lowest dose necessary to control plasma ammonia levels.[29]

12. Regulatory Status and Market Overview

12.1. Regulatory Approvals

Phenylbutyric acid, in its various salt and ester forms, has received regulatory approval from major health authorities for the treatment of UCDs.

• Sodium Phenylbutyrate:
• Buphenyl® (Horizon Therapeutics US): Approved by the U.S. Food and Drug Administration (FDA). NDA numbers include 020572 (Powder) and 020573 (Tablets).[17]
• Pheburane® (Immedica Pharma AB - EU; Medunik USA Inc. - US): Approved by the European Medicines Agency (EMA) under marketing authorisation EMEA/H/C/002500.[4] Also approved in other regions like Australia (Orpharma Pty Ltd).[26]
• Olpruva™ (Acer Therapeutics): Approved by the FDA. NDA number 214860.[17]
• Ammonaps® (Swedish Orphan Biovitrum AB): Serves as the reference medicinal product for Pheburane® in the EU.[4]
• Generic sodium phenylbutyrate formulations are also approved and available.[17]
• Glycerol Phenylbutyrate (Ravicti®) (Horizon Therapeutics):
• Approved by the FDA on February 1, 2013.[35]
• Approved by the EMA for the chronic management of UCDs in adult and pediatric patients (all ages per EMA; initial FDA approval was for ≥2 years, later expanded).[20]

12.2. Orphan Drug Designations

Given the rarity of UCDs, phenylbutyrate products have received orphan drug designations to incentivize their development and marketing.

• Sodium Phenylbutyrate: Designated as an orphan drug by the FDA for the treatment of UCDs.[21] It has also received orphan drug designations from the FDA for other indications, including as an adjunct in the treatment of acute promyelocytic leukemia and primary or recurrent malignant glioma.[54]
• Pheburane®: Was originally designated as an orphan medicine by the EMA for carbamoyl-phosphate-synthase-1 deficiency, citrullinaemia type 1, and ornithine-transcarbamylase deficiency. However, this designation was later removed from the Community register of orphan medicinal products at the request of the marketing authorisation holder.[4] The reasons for this withdrawal are not specified in the provided documents but could relate to market strategy or fulfillment of post-marketing orphan drug requirements.
• Ravicti® (Glycerol Phenylbutyrate): Has received orphan designation from the EMA for the treatment of UCDs.[35]

The granting of orphan drug status provides various incentives, including market exclusivity for a defined period and fee reductions, to encourage the development of treatments for rare diseases.[55] The withdrawal of Pheburane's orphan status is a notable regulatory event, potentially reflecting strategic decisions by the marketing authorization holder once the product was established or if the conditions for orphan maintenance were no longer applicable.

12.3. Marketed Products and Developers/Marketers

A number of pharmaceutical companies are involved in the development and marketing of phenylbutyrate-based products:

• Buphenyl®: Horizon Therapeutics (following acquisition of Ucyclyd Pharma, which had acquired it from Medicis Pharmaceutical Corp.).[16]
• Pheburane®: Currently held by Immedica Pharma AB in the EU. Medunik USA Inc. markets it in the US. Orpharma Pty Ltd is associated with its marketing in Australia. Lucane Pharma was an earlier developer/marketer.[4]
• Olpruva™: Acer Therapeutics.[17]
• Ravicti®: Horizon Therapeutics.[20]
• Generic Sodium Phenylbutyrate: Marketed by several companies, including Endo Operations, Sigmapharm Labs LLC, Alvogen, and Glenmark Pharmaceuticals Ltd.[17]

The market for UCD treatments involving phenylbutyrate is characterized by a mix of established branded products, newer formulations aimed at improving patient experience, and cost-saving generic alternatives. This creates a dynamic therapeutic landscape where clinicians and payers must weigh efficacy, tolerability, patient-specific needs, and economic factors. The increasing incidence of UCDs and MSUD (Maple Syrup Urine Disease, though phenylbutyrate is not a primary treatment for MSUD, it's mentioned in market reports in this context) and growing awareness are projected to drive market growth for sodium phenylbutyrate, with North America and Europe being significant markets.[17]

13. Conclusion and Future Perspectives

13.1. Summary of Phenylbutyric Acid's Profile

Phenylbutyric acid is a versatile pharmacological agent with a well-entrenched, life-saving role as a nitrogen-scavenging drug in the chronic management of urea cycle disorders. Its mechanism in UCDs involves its conversion to phenylacetate, which conjugates with glutamine to form phenylacetylglutamine, an alternative vehicle for waste nitrogen excretion. This action effectively reduces hyperammonemia, a hallmark of UCDs. Beyond this primary indication, phenylbutyric acid exhibits distinct biological activities as a histone deacetylase (HDAC) inhibitor and a chemical chaperone. These properties have spurred investigations into its therapeutic potential for a wide array of other conditions, including cystic fibrosis, certain cancers, hemoglobinopathies, and various neurodegenerative and inflammatory diseases.

However, the clinical translation of these investigational uses has faced challenges. While preclinical studies often show promise, particularly for its chaperone and HDAC inhibitory effects, demonstrating robust and consistent clinical efficacy in complex diseases like solid tumors has proven difficult. The pharmacokinetic profile of phenylbutyrate is characterized by rapid absorption and metabolism, with a relatively short half-life for the parent drug and its active metabolite, phenylacetate. Formulations have evolved from basic sodium salts with palatability and sodium load issues to taste-masked granules and a glycerol ester prodrug (glycerol phenylbutyrate) designed to improve compliance and reduce sodium intake. Safety considerations are significant, with potential neurotoxicity from phenylacetate accumulation, risk of hypokalemia, and concerns related to sodium load with certain formulations being paramount.

13.2. Unmet Needs and Ongoing Research

Despite the availability of phenylbutyrate-based therapies, significant unmet needs persist in the management of UCDs. While survival has dramatically improved, long-term neurocognitive outcomes remain a major concern, emphasizing the need for strategies that not only control ammonia but also protect the brain from both acute and chronic effects of the metabolic derangement. Patient adherence to lifelong therapy, which includes complex dietary restrictions and medication regimens, is another challenge that newer, more palatable, and potentially less burdensome formulations aim to address.

For its investigational uses, the primary unmet need is the translation of promising preclinical findings into tangible clinical benefits. For cystic fibrosis, more effective CFTR modulators are sought. In oncology, the limited success of phenylbutyric acid in solid tumors highlights the need for a better understanding of its context-dependent effects and potentially for more targeted HDAC inhibitors or combination strategies. In hemoglobinopathies and neurodegenerative diseases, demonstrating clinically meaningful and sustained improvements with acceptable long-term safety remains the goal of ongoing research.

13.3. Future Perspectives

The future development and application of phenylbutyric acid and its derivatives are likely to proceed along several fronts:

• Optimization for UCDs: Continued research into optimizing dosing strategies, potentially guided by pharmacogenomics or more precise biomarkers like urinary PAGN or plasma PAA levels, could help personalize therapy to maximize nitrogen scavenging while minimizing toxicity. The development of formulations with even more favorable pharmacokinetic profiles (e.g., extended-release to reduce dosing frequency or further improve overnight ammonia control) may also enhance treatment outcomes and adherence.
• Targeting Specific Mechanisms for Other Diseases: Given its multiple mechanisms of action, future research may focus on developing derivatives or analogues of phenylbutyric acid that are more selective or potent for either HDAC inhibition or chemical chaperone activity. For example, a derivative with enhanced HDAC inhibitory potency and improved tumor penetration could be more successful in oncology. Conversely, a derivative optimized for chemical chaperone activity with minimal HDAC effects might be preferable for certain neurodegenerative or protein-misfolding disorders. This approach could help to harness the desired therapeutic effect while minimizing off-target activities that might contribute to side effects or limit efficacy.
• Combination Therapies: In complex diseases like cancer or neurodegenerative disorders, phenylbutyric acid (or its derivatives) might find a role as part of combination regimens. For instance, its HDAC inhibitory effects could sensitize cancer cells to other chemotherapeutic agents or immunotherapies. Its chemical chaperone properties might be combined with therapies that target other aspects of proteinopathy or ER stress.
• Elucidating Context-Dependent Effects: A deeper understanding of how phenylbutyric acid's effects vary depending on cellular context, disease state, and drug concentration is crucial. For example, clarifying the factors that determine whether HDAC inhibition by phenylbutyric acid leads to anti-proliferative or pro-migratory effects in cancer cells could inform patient selection or the design of more effective treatment protocols.

In conclusion, phenylbutyric acid is a valuable therapeutic agent for UCDs and a fascinating molecule with diverse biological activities that hold promise for other conditions. Realizing this broader potential will require continued research to overcome current limitations, optimize its delivery and action, and better understand its complex pharmacology in various disease settings.

Works cited

1. Phenylbutyric acid: Uses, Interactions, Mechanism of Action ..., accessed May 19, 2025, https://go.drugbank.com/drugs/DB06819
2. Phenylbutyric acid | C10H12O2 | CID 4775 - PubChem, accessed May 19, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Phenylbutyric-acid
3. Phenylbutyric acid | C10H12O2 | CID 4775 - PubChem, accessed May 19, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Phenylbutyrate
4. Pheburane | European Medicines Agency (EMA), accessed May 19, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/pheburane
5. Phenylbutyric Acid Overview, accessed May 19, 2025, https://ontosight.ai/glossary/term/phenylbutyric-acid-overview--67a216ddc445bf945aeb907f
6. 4-phenylbutyric acid promotes migration of gastric cancer cells by ..., accessed May 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7574398/
7. 4-PBA upregulated IL-8 expression and IL-8 pathway activation through... - ResearchGate, accessed May 19, 2025, https://www.researchgate.net/figure/4-PBA-upregulated-IL-8-expression-and-IL-8-pathway-activation-through-HDAC-activity_fig5_337843003
8. Evidence that Chemical Chaperone 4-Phenylbutyric Acid Binds to ..., accessed May 19, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133012
9. Chemical chaperone 4-phenylbutyric acid protects H9c2 cardiomyocytes from ischemia/reperfusion injury by attenuating endoplasmic reticulum stress-induced apoptosis - Spandidos Publications, accessed May 19, 2025, https://www.spandidos-publications.com/10.3892/mmr.2016.5063
10. 4-Phenylbutyric acid | CAS 1821-12-1 | SCBT, accessed May 19, 2025, https://www.scbt.com/p/4-phenylbutyric-acid-1821-12-1
11. 4-Phenylbutyric acid 99 1821-12-1 - Sigma-Aldrich, accessed May 19, 2025, https://www.sigmaaldrich.com/US/en/product/aldrich/p21005
12. Determination of phenylbutyric acid and its metabolite phenylacetic acid in different tissues of mouse by liquid chromatography with tandem mass spectrometry and its application in drug tissue distribution | Request PDF - ResearchGate, accessed May 19, 2025, https://www.researchgate.net/publication/230581157_Determination_of_phenylbutyric_acid_and_its_metabolite_phenylacetic_acid_in_different_tissues_of_mouse_by_liquid_chromatography_with_tandem_mass_spectrometry_and_its_application_in_drug_tissue_distrib
13. Sodium Phenylbutyrate Powder: Package Insert / Prescribing Info - Drugs.com, accessed May 19, 2025, https://www.drugs.com/pro/sodium-phenylbutyrate-powder.html
14. BUPHENYL® (sodium phenylbutyrate) Tablets BUPHENYL® (sodium phenylbutyrate) Powder - accessdata.fda.gov, accessed May 19, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020572s016,020573s015lbl.pdf
15. BUPHENYL® (sodium phenylbutyrate) Patient Support Program | Amgen By Your Side, accessed May 19, 2025, https://www.amgenbyyourside.com/buphenyl/patient
16. BUPHENYL® Resources | Amgen By Your Side HCP, accessed May 19, 2025, https://www.amgenbyyourside.com/buphenyl/hcp/resources
17. Generic SODIUM PHENYLBUTYRATE INN entry, drug patent and freedom to operate, accessed May 19, 2025, https://www.drugpatentwatch.com/p/generic/sodium+phenylbutyrate
18. BUPHENYL® (sodium phenylbutyrate) Tablets, accessed May 19, 2025, https://www.ravictihcp.com/-/media/Themes/Horizon/Ravictihcp/Ravictihcp/Documents/BUPHENYL-Prescribing-Information.PDF
19. CP.PHAR.208 Sodium phenylbutyrate (Buphenyl, Pheburane) - Delaware First Health, accessed May 19, 2025, https://www.delawarefirsthealth.com/content/dam/centene/delaware/Policies/DrugPolicies/DrugPoliciesS/CP.PHAR.208%20Sodium%20phenylbutyrate%20(Buphenyl%20Pheburane)%2008.28.22.pdf
20. www.eocco.com, accessed May 19, 2025, https://www.eocco.com/-/media/EOCCO/PDFs/Formulary/Urea-Cycle-Disorder.pdf
21. Sodium Phenylbutyrate Monograph for Professionals - Drugs.com, accessed May 19, 2025, https://www.drugs.com/monograph/sodium-phenylbutyrate.html
22. Generic Buphenyl Availability - Drugs.com, accessed May 19, 2025, https://www.drugs.com/availability/generic-buphenyl.html
23. Urea Cycle Disorders Prior Authorization Program Summary - provider.bcbsal.org, accessed May 19, 2025, https://providers.bcbsal.org/portal/documents/10226/299839/Urea+Cycle+Disorders+Prior+Authorization+Program+Summary/6f2e25e9-a13e-46b1-ae55-782215def400?version=1.1
24. Pheburane, INN-sodium phenylbutyrate, accessed May 19, 2025, https://ec.europa.eu/health/documents/community-register/2017/20170522137843/anx_137843_en.pdf
25. Pheburane: Package Insert / Prescribing Information - Drugs.com, accessed May 19, 2025, https://www.drugs.com/pro/pheburane.html
26. Australian Public Assessment Report for Sodium phenylbutyrate, accessed May 19, 2025, https://www.tga.gov.au/sites/default/files/auspar-sodium-phenylbutyrate-180123.pdf
27. Sodium phenylbutyrate - Therapeutic Goods Administration (TGA), accessed May 19, 2025, https://www.tga.gov.au/sites/default/files/auspar-sodium-phenylbutyrate-180123-pi.docx
28. Ammonaps 500 mg tablets - Summary of Product Characteristics (SmPC) - (emc) | 10986, accessed May 19, 2025, https://www.medicines.org.uk/emc/product/10986/smpc
29. www.accessdata.fda.gov, accessed May 19, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214860s000lbl.pdf
30. Sodium phenylbutyrate (oral route) - Mayo Clinic, accessed May 19, 2025, https://www.mayoclinic.org/drugs-supplements/sodium-phenylbutyrate-oral-route/description/drg-20066057
31. Ammonia control in children with urea cycle disorders (UCDs); Phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate, accessed May 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4880058/
32. Ravicti (glycerol phenylbutyrate) dosing, indications, interactions ..., accessed May 19, 2025, https://reference.medscape.com/drug/ravicti-glycerol-phenylbutyrate-999807
33. Urea Cycle Disorders - OHP Preferred Drug List : Oregon Health Plan, accessed May 19, 2025, http://www.orpdl.org/durm/meetings/meetingdocs/2024_12_05/archives/2024_12_05_UreaCycle_Review.pdf
34. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate | Request PDF - ResearchGate, accessed May 19, 2025, https://www.researchgate.net/publication/230826459_Ammonia_control_and_neurocognitive_outcome_among_urea_cycle_disorder_patients_treated_with_glycerol_phenylbutyrate
35. Glycerol Phenylbutyrate | C33H38O6 | CID 10482134 - PubChem, accessed May 19, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/HPN-100
36. A randomized trial to study the comparative efficacy of ..., accessed May 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5924481/
37. 203284Orig1s000 - accessdata.fda.gov, accessed May 19, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203284Orig1s000CrossR.pdf
38. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RAVICTI safely and effec, accessed May 19, 2025, https://www.ravictihcp.com/-/media/Themes/Horizon/Ravictihcp/Ravictihcp/Documents/RAVICTI-Prescribing-Information.pdf
39. Sodium Phenylbutyrate Market Size and Forecast, 2025-2032 - Coherent Market Insights, accessed May 19, 2025, https://www.coherentmarketinsights.com/market-insight/sodium-phenylbutyrate-market-6052
40. Conjugation of phenylacetate with glutamine | Pathway - PubChem, accessed May 19, 2025, https://pubchem.ncbi.nlm.nih.gov/pathway/REACTOME:R-HSA-177162
41. CHEBI:17884 - N 2 -phenylacetyl-L-glutamine - EMBL-EBI, accessed May 19, 2025, https://www.ebi.ac.uk/chebi/searchId.do?chebiId=17884
42. 4-Phenylbutyric acid modulates Connexin 43 expression restricting ..., accessed May 19, 2025, https://www.biorxiv.org/content/10.1101/2024.12.10.627737v1.full-text
43. Showing metabocard for ... - Human Metabolome Database, accessed May 19, 2025, https://www.hmdb.ca/metabolites/HMDB0000543
44. 4-phenylbutyric acid promotes migration of gastric cancer cells by histone deacetylase inhibition-mediated IL-8 upregulation - ResearchGate, accessed May 19, 2025, https://www.researchgate.net/publication/337843003_4-phenylbutyric_acid_promotes_migration_of_gastric_cancer_cells_by_histone_deacetylase_inhibition-mediated_IL-8_upregulation
45. 4-Phenylbutyric acid mitigates ER stress-induced ... - Oxford Academic, accessed May 19, 2025, https://academic.oup.com/hmg/article/34/1/32/7889395
46. Inhibition of Endoplasmic Reticulum Stress Using 4-phenylbutyric ..., accessed May 19, 2025, https://acrabstracts.org/abstract/inhibition-of-endoplasmic-reticulum-stress-using-4-phenylbutyric-acid-ameliorates-the-severity-of-collagen-induced-arthritis-in-mice-via-attenuation-of-proliferation-and-inflammatory-responses-of-syno/
47. Clinical Trials Finder - Cystic Fibrosis Foundation, accessed May 19, 2025, https://www.cff.org/trials/finder
48. Pharmacological treatment of the biochemical defect in cystic ..., accessed May 19, 2025, https://publications.ersnet.org/content/erj/17/6/1314
49. Sodium phenylbutyrate and Alcohol/Food Interactions - Drugs.com, accessed May 19, 2025, https://www.drugs.com/food-interactions/sodium-phenylbutyrate.html
50. Ornithine Transcarbamylase Deficiency - Symptoms, Causes, Treatment | NORD, accessed May 19, 2025, https://rarediseases.org/rare-diseases/ornithine-transcarbamylase-deficiency/
51. Thalassemia Clinical Trials Currently Available to U.S. Patients | CAF, accessed May 19, 2025, https://thalassemia.org/Thalassemia-Clinical-Trials-Currently-Available-to-U-S-Patients
52. 4-Phenylbutyric Acid Protects Ethanol-induced Damage in the Developing Mouse Brain, accessed May 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6318008/
53. Phenylbutyrate: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed May 19, 2025, https://www.rxlist.com/phenylbutyrate/generic-drug.htm
54. Antineoplaston Therapy and Sodium Phenylbutyrate, accessed May 19, 2025, https://member.myhealthtoolkitks.com/web/public/brands/medicalpolicy/external-policies/antineoplaston-therapy-and-sodium-phenylbutyrate/
55. Orphan designation: Overview | European Medicines Agency (EMA), accessed May 19, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/orphan-designation-overview