Journal
MOLECULAR GENETICS AND METABOLISM
Volume 110, Issue 4, Pages 446-453Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2013.09.017
Keywords
BUPHENYL; Glycerol phenylbutyrate; HPN-100; Neurological adverse events; RAVICTI; Sodium phenylbutyrate
Funding
- Hyperion
- 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 [UURR31973]
- Mount Sinai School of Medicine [UL1RR29887]
- Oregon Health & Science University [UL1RR24140]
- Stanford University [UL1RR25744]
- Tufts University [UL1 RR25752]
- University of California, Los Angeles [UL1RR33176]
- University of Colorado [UL1 RR25780]
- University of Florida [UURR29890]
- University of Minnesota [UL1RR33183]
- University of Pittsburgh [UL1RR24153, UUTR000005]
- University of Utah [UL1RR25764]
- University of Washington [UL1RR25014]
- Urea Cycle Disorders Consortium (NIH) [U54RR019453]
- O'Malley Foundation
- Kettering Fund
- National Urea Cycle Disorders Foundation Research Fellowship
Ask authors/readers for more resources
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. PM is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PM plasma levels >= 500 mu g/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PM intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PM pro-drugs as well as approaches to identifying patients most likely to experience high PM levels. Methods: The relationship between nervous system AEs, PM levels and the ratio of plasma PM 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 PM to PAGN was analyzed with respect to its utility in identifying patients at risk of high PM values. Results: Only 0.2% (11) of 4683 samples exceeded 500 mu g/ml. There was no relationship between neurological AEs and PM levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PM levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PM levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in mu g/mL) in a random blood draw identified patients at risk for PM levels > 500 mu g/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. (C) 2013 Elsevier Inc. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available