Urinary excretion and metabolism of miglustat and valproate in patients with Niemann-Pick Type C1 disease: one- and two-dimensional solution-state 1H NMR studies
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 1H 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 1H 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.
Citation : Probert, F. et al. (2015) Urinary excretion and metabolism of miglustat and valproate in patients with Niemann-Pick Type C1 disease: one- and two-dimensional solution-state 1H NMR studies. Journal of Pharmaceutical and Biomedical Analysis, Accepted Manuscript, Available online 13 August 2015.
ISSN : 0731-7085
Research Institute : Leicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)
- Leicester School of Pharmacy