title: Urinary excretion and metabolism of miglustat and valproate in patients with Niemann-Pick type C1 disease: One- and two-dimensional solution-state (1)H NMR studies.
abstract: Niemann-Pick type C1 (NP-C1) disease is a neurodegenerative lysosomal storage disease for which the only approved therapy is miglustat (MGS). In this study we explored the applications and value of both one- and two-dimensional high-resolution NMR analysis strategies to the detection and quantification of MGS and its potential metabolites in urine samples collected from NP-C1 disease patients (n=47), and also applied these techniques to the analysis of the anticonvulsant drug valproate and one of its major metabolites in ca. 30% of these samples (i.e. from those who were also receiving this agent for the control of epileptic seizures). A combination of high-resolution 1D and 2D TOCSY/NOESY techniques confirmed the identity of MGS in the urinary (1)H NMR profiles of NP-C1 patients treated with this agent (n=25), and its quantification was readily achievable via electronic integration of selected 1D resonance intensities. However, this analysis provided little or no evidence for its metabolism in vivo, observations consistent with those acquired in corresponding experiments performed involving an in vitro microsomal system. Contrastingly, the major valproate metabolite 1-O-valproyl-β-glucuronide was readily detectable and quantifiable in 14/47 of the urine samples investigated, despite some resonance overlap problems (identification of this agent was confirmed by experiments involving equilibration of these samples with β-glucuronidase, a process liberating free valproate). In order to facilitate and validate the detection of MGS in urine specimens, full assignments of the (1)H NMR spectra of MGS in both buffered aqueous (pH 7.10) and deuterated methanol solvent systems were also made. The pharmacological and bioanalytical significance of data acquired are discussed, with special reference to the advantages offered by high-resolution NMR analysis.
authors.affiliation: Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
authors.forename: Fay
authors.initials: F
authors.lastname: Probert
authors.affiliation: Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
authors.forename: Victor
authors.initials: V
authors.lastname: Ruiz-Rodado
authors.affiliation: Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK; School of Pharmacy, China Pharmaceutical University, Jiangning Campus, 639 Longmian Avenue, Jiangning District, Nanjing, Jiangsu 211198 China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Danielle
authors.initials: D
authors.lastname: te Vruchte
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Tim D W
authors.initials: TD
authors.lastname: Claridge
authors.affiliation: Department of Chemistry, Loughborough University, Loughborough, LE11 3TU, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Edgar
authors.affiliation: Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
authors.forename: Anna Zonato
authors.initials: AZ
authors.lastname: Tocchio
authors.affiliation: Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Robin H
authors.initials: RH
authors.lastname: Lachmann
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.affiliation: Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK. Electronic address: mgrootveld@dmu.ac.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Grootveld
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use / Q000652:urine; D000818:Animals; D015331:Cohort Studies; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use / Q000652:urine; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy / Q000378:metabolism / Q000652:urine*; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000378:metabolism / Q000627:therapeutic use / Q000652:urine*
chemical_list: D004791:Enzyme Inhibitors; D011522:Protons; D017485:1-Deoxynojirimycin; D014635:Valproic Acid; C059896:miglustat
keywords: 1-O-Valproyl-β-glucuronide (53477719); Drug metabolism; Miglustat; Miglustat (CID 51634); NMR-based urinalysis; NP-C disease; TOCSY/NOESY NMR techniques; Valproate; Valproate (CID 3121)