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, Marwan Ghabril, R. S. Brown, K. DickinsonT. Moors, C. Norris, D. Coakley, D. A. Milikien, S. C. Nagamani, C. LeMons, B. Lee, B. F. Scharschmidt

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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
Pages (from-to)446-453
Number of pages8
JournalMolecular Genetics and Metabolism
Volume110
Issue number4
DOIs
StatePublished - 2013

Fingerprint

Inborn Urea Cycle Disorder
Hepatic Encephalopathy
Urea
Plasmas
phenylacetic acid
Blood

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

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

In: Molecular Genetics and Metabolism, Vol. 110, No. 4, 2013, p. 446-453.

Research output: Contribution to journalArticle

Mokhtarani, M, Diaz, GA, Rhead, W, Berry, SA, Lichter-Konecki, U, Feigenbaum, A, Schulze, A, Longo, N, Bartley, J, Berquist, W, Gallagher, R, Smith, W, McCandless, SE, Harding, C, Rockey, DC, Vierling, JM, Mantry, P, Ghabril, M, Brown, RS, Dickinson, K, Moors, T, Norris, C, Coakley, D, Milikien, DA, Nagamani, SC, LeMons, C, Lee, B & Scharschmidt, BF 2013, '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', Molecular Genetics and Metabolism, vol. 110, no. 4, pp. 446-453. https://doi.org/10.1016/j.ymgme.2013.09.017
Mokhtarani, M. ; Diaz, G. A. ; Rhead, W. ; Berry, S. A. ; Lichter-Konecki, U. ; Feigenbaum, A. ; Schulze, A. ; Longo, N. ; Bartley, J. ; Berquist, W. ; Gallagher, R. ; Smith, W. ; McCandless, S. E. ; Harding, C. ; Rockey, D. C. ; Vierling, J. M. ; Mantry, P. ; Ghabril, Marwan ; Brown, R. S. ; Dickinson, K. ; Moors, T. ; Norris, C. ; Coakley, D. ; Milikien, D. A. ; Nagamani, S. C. ; LeMons, C. ; Lee, B. ; Scharschmidt, B. F. / 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. In: Molecular Genetics and Metabolism. 2013 ; Vol. 110, No. 4. pp. 446-453.
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abstract = "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.",
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author = "M. Mokhtarani and Diaz, {G. A.} and W. Rhead and Berry, {S. A.} and U. Lichter-Konecki and A. Feigenbaum and A. Schulze and N. Longo and J. Bartley and W. Berquist and R. Gallagher and W. Smith and McCandless, {S. E.} and C. Harding and Rockey, {D. C.} and Vierling, {J. M.} and P. Mantry and Marwan Ghabril and Brown, {R. S.} and K. Dickinson and T. Moors and C. Norris and D. Coakley and Milikien, {D. A.} and Nagamani, {S. C.} and C. LeMons and B. Lee and Scharschmidt, {B. F.}",
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doi = "10.1016/j.ymgme.2013.09.017",
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TY - JOUR

T1 - 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

AU - Mokhtarani, M.

AU - Diaz, G. A.

AU - Rhead, W.

AU - Berry, S. A.

AU - Lichter-Konecki, U.

AU - Feigenbaum, A.

AU - Schulze, A.

AU - Longo, N.

AU - Bartley, J.

AU - Berquist, W.

AU - Gallagher, R.

AU - Smith, W.

AU - McCandless, S. E.

AU - Harding, C.

AU - Rockey, D. C.

AU - Vierling, J. M.

AU - Mantry, P.

AU - Ghabril, Marwan

AU - Brown, R. S.

AU - Dickinson, K.

AU - Moors, T.

AU - Norris, C.

AU - Coakley, D.

AU - Milikien, D. A.

AU - Nagamani, S. C.

AU - LeMons, C.

AU - Lee, B.

AU - Scharschmidt, B. F.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - BUPHENYL

KW - Glycerol phenylbutyrate

KW - HPN-100

KW - Neurological adverse events

KW - RAVICTI

KW - Sodium phenylbutyrate

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