Phenylbutyrate Metabolite Analysis

This assay measures the levels of phenylacetylglutamine (PAG) and its upstream metabolites phenylbutyrate and phenylacetate in plasma.

A hallmark of most urea cycle disorders (UCDs) is the toxic accumulation of ammonia that ultimately leads to several clinical features, including cognitive impairment. Accordingly, treatment for UCD patients involves daily oral intake of ammonia scavenging drugs, including sodium phenylbutyrate (SPB) and/or glycerol phenylbutyrate (GPB) which go by the trade names Buphenyl and Raviciti, respectively. Once consumed, both SPB and GPB are converted to phenylacetate, a compound that scavenges ammonia through the formation of the urine excreted metabolite phenylacetylglutamine (PAG) (1-3). Sodium phenylbutyrate is also in phase I clinical trials for the treatment of Parkinson's disease to slow the progression of the disease and to reduce the death of dopaminergic neurons (4, 5).

The key to successful treatment of UCDs is the accurate monitoring of patient compliance and ammonia removal. Unfortunately, even under optimal conditions, a patient's daily plasma ammonia levels can fluctuate by as much as 10-fold, rendering it an inexact diagnostic value for clinical management (2, 3). Instead, urinary excretion of PAG has been proposed as a dosing biomarker based on the strong correlation between urine excreted PAG and daily intake of phenylbutyrate (3). To allow comprehensive monitoring of UCD patients, our assays measure urine and plasma levels of PAG and its upstream precursors phenylbutyrate and phenylacetate.

This test is appropriate for patients with urea cycle disorders being treated with oral ammonia scavenging drugs.

This test can also be performed on urine (test code 4651).

1. Lee B, et al. (2010) Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: safety, pharmacokinetics, and ammonia control. Molecular genetics and metabolism 100(3):221-228.
2. Lichter-Konecki U, et al. (2011) Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate. Molecular genetics and metabolism 103(4):323-329.
3. Mokhtarani M, et al. (2012) Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders. Molecular genetics and metabolism 107(3):308-314.
4. Roy A, et al. (2012) Sodium phenylbutyrate controls neuroinflammatory and antioxidant activities and protects dopaminergic neurons in mouse models of Parkinson's disease. PloS one 7(6): e38113.
5. Zhou W, et al. (2011) Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease. The Journal of biological chemistry 286(17):14941-14951.