Document Detail


Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders.
MedLine Citation:
PMID:  22958974     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
STUDY DESIGN: These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine.
RESULTS: Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control.
CONCLUSION: The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.
Authors:
M Mokhtarani; G A Diaz; W Rhead; U Lichter-Konecki; J Bartley; A Feigenbaum; N Longo; W Berquist; S A Berry; R Gallagher; D Bartholomew; C O Harding; M S Korson; S E McCandless; W Smith; J Vockley; S Bart; D Kronn; R Zori; S Cederbaum; N Dorrani; J L Merritt; Sandesh Sreenath-Nagamani; M Summar; C Lemons; K Dickinson; D F Coakley; T L Moors; B Lee; B F Scharschmidt
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-18
Journal Detail:
Title:  Molecular genetics and metabolism     Volume:  107     ISSN:  1096-7206     ISO Abbreviation:  Mol. Genet. Metab.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-29     Completed Date:  2013-03-27     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  9805456     Medline TA:  Mol Genet Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  308-14     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
Hyperion Therapeutics, 601 Gateway Blvd, Suite 200, South San Francisco, CA 94080, USA. Masoud.mokhtarani@hyperiontx.com
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Ammonia / blood,  urine*
Biomarkers, Pharmacological / blood,  urine
Child
Cross-Over Studies
Drug Administration Schedule
Female
Glutamine / analogs & derivatives*,  blood,  urine
Glycerol / analogs & derivatives*,  blood,  pharmacokinetics,  urine
Humans
Male
Phenylacetates / blood,  urine*
Phenylbutyrates / blood,  pharmacokinetics,  urine*
Urea Cycle Disorders, Inborn / blood,  drug therapy*,  urine*
Grant Support
ID/Acronym/Agency:
M01 RR000071/RR/NCRR NIH HHS; M01RR00188/RR/NCRR NIH HHS; U54 HD061221/HD/NICHD NIH HHS; U54RR019453/RR/NCRR NIH HHS; UL1 RR024153/RR/NCRR NIH HHS; UL1 RR024989/RR/NCRR NIH HHS; UL1 RR029890/RR/NCRR NIH HHS; UL1 RR031973/RR/NCRR NIH HHS; UL1 TR000005/TR/NCATS NIH HHS; UL1 TR000067/TR/NCATS NIH HHS; UL1 TR000128/TR/NCATS NIH HHS; UL1 TR000423/TR/NCATS NIH HHS; UL1RR024989/RR/NCRR NIH HHS; UL1RR24140/RR/NCRR NIH HHS; UL1RR24153/RR/NCRR NIH HHS; UL1RR25014/RR/NCRR NIH HHS; UL1RR25744/RR/NCRR NIH HHS; UL1RR25752/RR/NCRR NIH HHS; UL1RR25764/RR/NCRR NIH HHS; UL1RR25780/RR/NCRR NIH HHS; UL1RR29887/RR/NCRR NIH HHS; UL1RR29890/RR/NCRR NIH HHS; UL1RR31973/RR/NCRR NIH HHS; UL1RR31988/RR/NCRR NIH HHS; UL1RR33176/RR/NCRR NIH HHS; UL1RR33183/RR/NCRR NIH HHS; UL1TR000005/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Biomarkers, Pharmacological; 0/Phenylacetates; 0/Phenylbutyrates; 103-82-2/phenylacetic acid; 28047-15-6/phenylacetylglutamine; 56-81-5/Glycerol; 56-85-9/Glutamine; 7664-41-7/Ammonia; ZH6F1VCV7B/glycerol phenylbutyrate
Comments/Corrections

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