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Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders.

ABSTRACT: Sodium phenylbutyrate (NaPBA) is a commonly used medication for the treatment of patients with urea cycle disorders (UCDs). Previous reports involving small numbers of patients with UCDs have shown that NaPBA treatment can result in lower plasma levels of the branched-chain amino acids (BCAA) but this has not been studied systematically. From a large cohort of patients (n=553) with UCDs enrolled in the Longitudinal Study of Urea Cycle Disorders, a collaborative multicenter study of the Urea Cycle Disorders Consortium, we evaluated whether treatment with NaPBA leads to a decrease in plasma BCAA levels. Our analysis shows that NaPBA use independently affects the plasma BCAA levels even after accounting for multiple confounding covariates. Moreover, NaPBA use increases the risk for BCAA deficiency. This effect of NaPBA seems specific to plasma BCAA levels, as levels of other essential amino acids are not altered by its use. Our study, in an unselected population of UCD subjects, is the largest to analyze the effects of NaPBA on BCAA metabolism and potentially has significant clinical implications. Our results indicate that plasma BCAA levels should to be monitored in patients treated with NaPBA since patients taking the medication are at increased risk for BCAA deficiency. On a broader scale, these findings could open avenues to explore NaPBA as a therapy in maple syrup urine disease and other common complex disorders with dysregulation of BCAA metabolism.

SUBMITTER: Burrage LC

PROVIDER: S-EPMC4177960 | biostudies-literature | 2014 Sep-Oct

REPOSITORIES: biostudies-literature

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Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders.

Burrage Lindsay C LC Jain Mahim M Gandolfo Laura L Lee Brendan H BH Nagamani Sandesh C S SC

Molecular genetics and metabolism 20140703 1-2

Sodium phenylbutyrate (NaPBA) is a commonly used medication for the treatment of patients with urea cycle disorders (UCDs). Previous reports involving small numbers of patients with UCDs have shown that NaPBA treatment can result in lower plasma levels of the branched-chain amino acids (BCAA) but this has not been studied systematically. From a large cohort of patients (n=553) with UCDs enrolled in the Longitudinal Study of Urea Cycle Disorders, a collaborative multicenter study of the Urea Cycl ...[more]

PMID: 25042691

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Project description:Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs).Protocol HPN-100-005 involved open label fixed-sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB dose with controlled diet. After 7 days on NaPBA or GPB, subjects underwent 24-hour blood sampling for ammonia and drug metabolite levels as well as measurement of 24-hour urinary phenyacetylglutamine (PAGN). Adverse events (AEs), safety labs and triplicate ECGs were monitored.Eleven subjects (9 OTC, 1 ASS, 1 ASL) enrolled and completed the switch-over from NaPBA (mean dose=12.4 g/d or 322 mg/kg/d; range=198-476 mg/kg/d) to GPB (mean dose=10.8 mL or 0.284 mL/kg/d or 313 mg/kg/d; range=192-449 mg/kg/d). Possibly-related AEs were reported in 2 subjects on NaPBA and 4 subjects on GPB. All were mild, except for one moderate AE of vomiting on GPB related to an intercurrent illness. No clinically significant laboratory or ECG changes were observed. Ammonia was lowest after overnight fast, peaked postprandially in the afternoon to early evening and varied widely over 24h with occasional values >100 ?mol/L without symptoms. Ammonia values were ~25% lower on GPB vs. NaPBA (p?0.1 for ITT and p<0.05 for per protocol population). The upper 95% confidence interval for the difference between ammonia on GPB vs. NaPBA in the ITT population (95% CI 0.575, 1.061; p=0.102) was less than the predefined non-inferiority margin of 1.25 and less than 1.0 in the pre-defined per-protocol population (95% CI 0.516, 0.958; p<0.05). No statistically significant differences were observed in plasma phenylacetic acid and PAGN exposure during dosing with GPB vs. NaPBA, and the percentage of orally administered PBA excreted as PAGN (66% for GPB vs. 69% for NaPBA) was very similar. GPB and NaPBA dose correlated best with urinary-PAGN.These findings suggest that GPB is at least equivalent to NaPBA in terms of ammonia control, has potential utility in pediatric UCD patients and that U-PAGN is a clinically useful biomarker for dose selection and monitoring.

Project description:Branched chained amino acids (BCAA) are essential components of the human diet and important nutrient signals, which regain particular interest in recent years with the avenue of metabolomics studies suggesting their potential role as biomarkers. There is now compelling evidence for predictive role of BCAA in progression of diabetes, but causality relationship is still debated concerning insulin resistance and genetic versus non-genetic pathogenesis. Mendelian randomization studies in large cohorts of diabetes indicated pathogenic role of PPM1K (protein phosphatase Mg2+/Mn2+ dependent 1K) on Chr 4q22.1 gene, encoding for a phosphatase that activates BCKDH (branched chain keto acid dehydrogenase) complex. Recent studies indicated that insulin rapidly and dose-dependently regulates gene expression of the same complex, but the relationship with systemic insulin resistance and glucose levels is complex. Rare genetic syndromes due to Mendelian mutations in key genes in BCAA catabolism may be good models to understand potential role of gene of BCAA catabolism. However, in studying complex disorders geneticists are faced to complete new aspects of metabolic regulation complicating understanding genetics of obesity, diabetes or metabolic syndrome. A review of genetic syndromes of BCAA metabolism suggests that insulin resistance is not present, except rare cases of methylmalonic aciduria due to MUT (methylmalonyl-coA mutase) gene on Chr 6p12.3. Another aspect that complicates understanding is the new role of central nervous system (CNS) in insulin resistance. For a long time the hypothalamic hunger/satiety neuronal system was considered a key site of nutrient regulation. Genes may also affect the brain rewarding system (BRS) that would regulate food intake by modulating the motivation to obtain food and considering hedonic properties. Nutrigenomic and nutrigenetic investigations taking into account concurrently BCAA intake, metabolic regulation and gene variation have large perspectives to merge genetic and nutritional understanding in complex disorders.

Dataset Information

Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders.

Publications

Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders.

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