Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio

M. Mokhtarani, G. A. Diaz, W. Rhead, S. A. Berry, U. Lichter-Konecki, A. Feigenbaum, A. Schulze, N. Longo, J. Bartley, W. Berquist, R. Gallagher, W. Smith, S. E. McCandless, C. Harding, D. C. Rockey, J. M. Vierling, P. Mantry, M. Ghabril, R. S. Brown, K. DickinsonT. Moors, C. Norris, D. Coakley, D. A. Milikien, S. C. Nagamani, C. LeMons, B. Lee, B. F. Scharschmidt

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30 Scopus citations


Background: Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels. ≥. 500. μg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. Methods: The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥. 2. months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. Results: Only 0.2% (11) of 4683 samples exceeded 500. μg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio. >. 2.5 (both in μg/mL) in a random blood draw identified patients at risk for PAA levels. >. 500. μg/ml. Conclusions: The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.

Original languageEnglish (US)
Pages (from-to)446-453
Number of pages8
JournalMolecular Genetics and Metabolism
Issue number4
StatePublished - Dec 2013

Bibliographical note

Funding Information:
The authors gratefully acknowledge and thank the efforts of the Study Coordinators and nursing staff who made these trials possible, including D. Bartholomew (Nationwide Children's Hospital), S. Cederbaum, D. Wong (University of California), J. Vockley (Children's Hospital of Pittsburgh), S. Bart, M. Al-Ibraham (SNBL), M.S. Korson (Tufts Medical Center), D. Kronn (Westchester Medical Center), R. Zori (University of Florida), J.L. Merritt (Seattle Children's Hospital), N. Schrager (Mount Sinai School of Medicine), A. Donovan, J. Crawford, Pediatric TRU Staff, K. Defouw, J. Balliet (The Medical College of Wisconsin), M. Keuth, N. O'Donnell (Long Beach Memorial Hospital), M. Hussain, E. Bailey, M. Ambreen (The Hospital for Sick Children, University of Toronto, ON, Canada), C. Bailey, A. Lang (The University of Utah), J. Perry, V. de Leon, A. Niemi, K. Cusmano (Stanford University),T. Carlson, J. Parker, S. Elsbecker (University of Minnesota), K. Simpson (Children's National Medical Center), K. Regis (Nationwide Children's Hospital), A. Behrend, T. Marrone, J. Martin (Oregon Health Sciences University), N. Dorrani (University of California, Los Angeles), M.B. Frohnapfel, S. Bergant, J. Haky, C. Tasi, C. Heggie (Case Western Reserve University), S. Mortenson (Maine Medical Center), S. Deward (Children's Hospital of Pittsburgh), S. Burr (Children's Hospital Colorado), K. Bart, C. Duggan (SNBL), K. Murray, C. Dedomenico (Tufts Medical Center), C. Gross (University of Florida), L. Brody (Seattle Children's Hospital), M. Mullins, S. Carter, A. Tran, J. Stuff, TCH General Clinical Research Center nursing staff (Baylor), B. McGuire (University of Alabama), D. Wolf (New York Medical College), C. O'Brien (University of Miami), R. O'Shea (Cleveland Clinic), I. Zupanets (National University of Pharmacy of MH of Ukraine), Kathy Lisam (Hyperion), as well as the Clinical and Translational Science Awards/General Clinical Research Center grants ( Baylor College of Medicine , M01RR00188 ; Case Western Reserve University , UL1RR024989 ; Clinical and Translational Science Institute at Children's National Medical Center NIH/NCRR , UL1RR31988 ; Medical College of Wisconsin , UL1RR31973 ; Mount Sinai School of Medicine , UL1RR29887 ; Oregon Health & Science University , UL1RR24140 ; Stanford University , UL1RR25744 ; Tufts University , UL1RR25752 ; University of California, Los Angeles , UL1RR33176 ; University of Colorado , UL1RR25780 ; University of Florida , UL1RR29890 ; University of Minnesota , UL1RR33183 ; University of Pittsburgh , UL1RR24153 , and UL1TR000005 ; University of Utah , UL1RR25764 ; University of Washington , UL1RR25014 ), the Urea Cycle Disorders Consortium ( NIH grant U54RR019453 ) and grants from the O'Malley Foundation and Kettering Fund which provided support. SCS. Nagamani is an awardee of the National Urea Cycle Disorders Foundation Research Fellowship. The authors also thank G. Enns (Stanford) for his comments on the manuscript.


  • Glycerol phenylbutyrate
  • HPN-100
  • Neurological adverse events
  • Sodium phenylbutyrate


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