Buphenyl (Sodium Phenylbutyrate) - Description and Clinical Pharmacology

[ bu'fen-əl ]
(sodium phenylbutyrate)

Rx Only

DESCRIPTION

BUPHENYL^® (sodium phenylbutyrate) Tablets for oral administration and BUPHENYL^® (sodium phenylbutyrate) Powder for oral, nasogastric, or gastrostomy tube administration contain sodium phenylbutyrate. Sodium phenylbutyrate is an off-white crystalline substance which is soluble in water and has a strong salty taste. Sodium phenylbutyrate also is freely soluble in methanol and practically insoluble in acetone and diethyl ether. It is known chemically as 4-phenylbutyric acid, sodium salt with a molecular weight of 186 and the molecular formula C₁₀H₁₁O₂Na.

Chemical Structure:

Each tablet of BUPHENYL contains 500 mg of sodium phenylbutyrate and the inactive ingredients microcrystalline cellulose NF, magnesium stearate NF, and colloidal silicon dioxide NF.

Each gram of BUPHENYL Powder contains 0.94 grams of sodium phenylbutyrate and the inactive ingredients calcium stearate NF, and colloidal silicon dioxide NF.

CLINICAL PHARMACOLOGY

Sodium phenylbutyrate is a pro-drug and is rapidly metabolized to phenylacetate. Phenylacetate is a metabolically-active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine. Phenylacetylglutamine then is excreted by the kidneys. On a molar basis, it is comparable to urea (each containing two moles of nitrogen). Therefore, phenylacetylglutamine provides an alternate vehicle for waste nitrogen excretion.

PHARMACOKINETICS

General

Pharmacokinetic studies have not been conducted in the primary patient population (neonates, infants, and children), but pharmacokinetic data were obtained from normal adult subjects.

Absorption

Peak plasma levels of phenylbutyrate occur within 1 hour after a single dose of 5 grams of sodium phenylbutyrate tablet with a C_max of 218 µg/mL under fasting conditions; peak plasma levels of phenylbutyrate occur within 1 hour after a single dose of 5 grams of sodium phenylbutyrate powder with a C_max of 195 µg/mL under fasting conditions. The effect of food on phenylbutyrate's absorption is unknown.

Disposition

The overall disposition of sodium phenylbutyrate and its metabolites has not been characterized fully. However, the drug is known to be metabolized to phenylacetate and subsequently to phenylacetylglutamine. Following oral administration of 5 grams (tablets), measurable plasma levels of phenylbutyrate and phenylacetate were detected 15 and 30 minutes after dosing, respectively, and phenylacetylglutamine was detected shortly thereafter. The pharmacokinetic parameters for phenylbutyrate for C_max (µg/mL), T_max (hours), and elimination half-life (hours) were 218, 1.35, and 0.77, respectively, and for phenylacetate were 48.5, 3.74, and 1.15, respectively.

Following oral administration of 5 grams of the powder, measurable plasma levels of phenylbutyrate and phenylacetate were detected 15 and 30 minutes after dosing, respectively, and phenylacetylglutamine was detected shortly thereafter. The pharmacokinetic parameters for phenylbutyrate for C_max (µg/mL), T_max (hours), and elimination half-life (hours) were 195, 1.00, and 0.76, respectively, and for phenylacetate were 45.3, 3.55, and 1.29, respectively.

The major sites for metabolism of sodium phenylbutyrate are the liver and kidney.

Excretion

A majority of the administered compound (approximately 80 – 100%) was excreted by the kidneys within 24 hours as the conjugation product, phenylacetylglutamine. For each gram of sodium phenylbutyrate administered, it is estimated that between 0.12 – 0.15 grams of phenylacetylglutamine nitrogen are produced.

Pharmacodynamics

In patients with urea cycle disorders, BUPHENYL^® decreased elevated plasma ammonia glutamine levels. It increases waste nitrogen excretion in the form of phenylacetylglutamine.

Special Populations

Gender

Significant gender differences were found in the pharmacokinetics of phenylbutyrate and phenylacetate, but not for phenylacetylglutamine. The pharmacokinetic parameters (AUC and C_max), for both plasma phenylbutyrate and phenylacetate were about 30 to 50 percent greater in females than in males.

Hepatic insufficiency

In patients who did not have urea cycle disorders but had impaired hepatic function, the metabolism and excretion of sodium phenylbutyrate were not affected. However, this information was obtained from unvalidated, uncontrolled case studies.