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Clin Pharmacol Drug Dev. 2013 Jul;2(3):278-84. doi: 10.1002/cpdd.18. Epub 2013 Mar 16.

Glycerol Phenylbutyrate in Patients With Cirrhosis and Episodic Hepatic Encephalopathy: A Pilot Study of Safety and Effect on Venous Ammonia Concentration.

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Indiana University School of Medicine, Indianapolis, IN, USA.
National University of Pharmacy, Kharkiv, Ukraine.
Baylor College of Medicine, Houston, TX, USA.
Liver Institute at Methodist Dallas Medical Center, Dallas, TX, USA.
University of Texas, Southwestern, Dallas, TX, USA.
New York Medical College, Valhalla, NY, USA.
Cleveland Clinic, Cleveland, OH, USA.
Hyperion Therapeutics, Inc., South San Francisco, CA, USA.


Glycerol tri-(4-phenylbutyrate) (glycerol phenylbutyrate, GPB, HPN-100) mediates waste nitrogen excretion through conjugation with glutamine to form phenylacetylglutamine which is excreted in urine. This pilot study was performed to assess tolerability and effect on venous ammonia concentration in patients with cirrhosis and hepatic encephalopathy (HE). Patients underwent one week of 6 mL (6.6 g) twice daily (BID). GPB dosing followed by 3 weeks of 9 mL (9.9 g) BID dosing and underwent repeated blood sampling for ammonia concentration and pharmacokinetics. Fifteen patients were enrolled. Ammonia concentrations were lowest after overnight fast and increased post-prandially. Fasting ammonia concentrations were lower on GPB compared to baseline, with a decrease on the eighth day of 6 mL BID dosing to 45.4 (27.9) µmol/L (ULN ∼48 µmol/L) (P < .05). Nine milliliters BID yielded similar lowering but was associated with more adverse events and higher phenylacetate (PAA) plasma concentrations (PAA Cmax of 144 [125] vs. 292 [224] µg/mL on 6 and 9 mL, respectively). GPB dosed at 6 mL BID lowered fasting ammonia levels in cirrhotic patients with HE as compared with baseline, was better tolerated than 9 mL BID, and is appropriate for further evaluation in patients with cirrhosis and episodic HE.


ammonia; cirrhosis; hepatic encephalopathy; phenylacetylglutamine; phenylbutyrate


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