Details

Autor(en) / Beteiligte

• 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, M.
• Brown, R.S.
• Dickinson, K.
• Moors, T.
• Norris, C.
• Coakley, D.
• Milikien, D.A.
• Nagamani, S.C.
• LeMons, C.
• Lee, B.
• Scharschmidt, B.F.

Titel

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

Ist Teil von

• Molecular genetics and metabolism, 2013-12, Vol.110 (4), p.446-453

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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≥500μg/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. 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 ≥2months 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. Only 0.2% (11) of 4683 samples exceeded 500μg/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>500μg/ml. 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. •Plasma PAA levels>500μg/dl associated with neurological AE in cancer patients.•Investigated trend of PAA and neurological AE in patients treated with PAA pro-drug.•Neurological AEs are transient in patients treated with PAA pro-drug.•High plasma PAA/PAGN identified patients are at risk for high PAA levels.•No correlation was found in patients between PAA levels and neurological AEs.