Summary of Study ST002297
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001471. The data can be accessed directly via it's Project DOI: 10.21228/M8KH70 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| Study ID | ST002297 |
| Study Title | Comprehensive biotransformation analysis of phenylalanine-tyrosine metabolism reveals alternative routes of metabolite clearance in nitisinone-treated alkaptonuria (Urine metabolomic analysis) |
| Study Type | Urine metabolomic analysis (study 2 of 2) |
| Study Summary | Background: Metabolomic analyses in alkaptonuria (AKU) have recently revealed alternative pathways in phenylalanine-tyrosine (phe-tyr) metabolism from biotransformation of homo-gentisic acid (HGA), the active molecule in this disease. The aim of this research was to study the phe-tyr metabolic pathway and whether the metabolites upstream of HGA, increased in nitisinone-treated patients, also undergo phase 1 and 2 biotransformation reactions. Methods: Metabolomic analyses were performed on serum and urine from patients partaking in the SONIA 2 phase 3 international randomised-controlled trial of nitisinone in AKU (EudraCT no. 2013-001633-41). Serum and urine samples were taken from the same patients at baseline (pre-nitisinone) then at 24 and 48 months on nitisinone treatment (patients N = 47 serum; 53 urine) or no treatment (patients N = 45 serum; 50 urine). Targeted feature extraction was per-formed to specifically mine data for the entire complement of theoretically predicted phase 1 and 2 biotransformation products derived from phenylalanine, tyrosine, 4-hydroxyphenylpyruvic acid and 4-hydroxyphenyllactic acid, in addition to phenylalanine-derived metabolites with known increases in phenylketonuria. Results: In total, we ob-served 13 phase 1 and 2 biotransformation products from phenylalanine through to HGA. Each of these products were observed in urine and two were detected in serum. The derivatives of the metabolites upstream of HGA were markedly increased in urine of nitisinone-treated patients (fold change 1.2-16.2) and increases in 12 of these compounds were directly proportional to the degree of nitisinone-induced hypertyrosinaemia (correlation coefficient with serum tyrosine = 0.2-0.7). Increases in the urinary phenylalanine metabolites were also observed across consecutive visits in the treated group. Conclusions: Nitisinone treatment results in marked increases in a wider network of phe-tyr metabolites than shown before. This network comprises alternative biotransformation products from the major metabolites of this pathway, produced by reactions including hydration (phase 1) and bioconjugation (phase 2) of acetyl, methyl, acetylcysteine, glucuronide, glycine and sulfate groups. We propose that these alternative routes of phe-tyr metabolism, predominantly in urine, minimise tyrosinaemia as well as phenylalanaemia. |
| Institute | University of Liverpool Institute of Life Course & Medical Sciences |
| Department | Department of Musculoskeletal & Ageing Science |
| Last Name | Brendan |
| First Name | Norman |
| Address | William Henry Duncan Building, 6 West Derby Street, Liverpool, UK. L7 8TX |
| bnorman@liverpool.ac.uk | |
| Phone | +447809606497 |
| Submit Date | 2022-09-28 |
| Num Groups | 2 |
| Total Subjects | 103 |
| Num Males | 65 |
| Num Females | 38 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | d |
| Analysis Type Detail | LC-MS |
| Release Date | 2022-10-14 |
| Release Version | 1 |
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Treatment:
| Treatment ID: | TR002395 |
| Treatment Summary: | Samples studied were from patients partaking in the SONIA 2 clinical trial of nitisinone in AKU. SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study undertaken at three study sites; Liverpool (UK), Paris (France) and Piešťany (Slovakia). The details and outcomes of the trial are published (1). Serum and urine samples were collected from participants at baseline (pre-treatment) then at 3 months and 1, 2, 3 and 4 years on 10 mg oral daily nitisinone (Orfadin®) treatment or no treatment. The serum and urine samples from visit 1 (baseline; pre-treatment), visit 4 (2 years), visit 6 (4 years) underwent metabolomic analysis. In this study, only the data from patients with samples available for these three time points were included; 53 and 50 patients in treated and untreated groups respectively for urine, and 47 and 45 patients in treated and untreated groups respectively for serum. Reference: (1) Ranganath, L.R.; Psarelli, E.E.; Arnoux, J.B.; Braconi, D.; Briggs, M.; Bröijersén, A.; Loftus, N.; Bygott, H.; Cox, T.F.; Davison, A.S.; et al. Efficacy and Safety of Once-Daily Nitisinone for Patients with Alkaptonuria (SONIA 2): An International, Multicentre, Open-Label, Randomised Controlled Trial. Lancet Diabetes Endocrinol. 2020, 8, 762–772, doi:10.1016/S2213-8587(20)30228-X. |
| Treatment Protocol ID: | Clinical trial ID: EudraCT no. 2013-001633-41 |
| Treatment Compound: | Nitisinone (NTBC) |
| Treatment Dose: | 10 mg daily |
| Treatment Doseduration: | 48 months total |
