Influence of the N-acetylation polymorphism on the metabolism of talampanel

An investigation in fasted and fed subjects genotyped for NAT2 variants

Peter Buchwald, A. Juhász, C. Bell, M. Pátfalusi, P. Kovács, G. Hochhaus, J. Howes, N. Bodor

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Talampanel is a 2,3-benzodiazepine-type allosteric (noncompetitive) AMPA-antagonist currently being developed as an orally active, broad-spectrum anticonvulsant. Here, a detailed study of its N-acetylation in humans is presented using plasma concentration data of both TLP and its N-acetyl metabolite obtained from healthy volunteers (n = 28) genotyped for N-acetyltansferase NAT2 isozymes. Plasma samples were obtained for up to 48 h after a single oral dose of 75 mg TLP both in fasted and in fed subjects. A perfect correspondence could be established between the phenotype inferred before the study from genotyping and that determined after the study by using plasma metabolite-to-parent molar ratios confirming that this route of metabolism is indeed mediated by NAT2. Analysis of the data has been performed using both noncompartmental analysis and a custom-built, unified parent-metabolite PK model, which incorporates three different acetylation rates according to the genotype-based classification of each subject as slow, intermediate, or fast acetylator to simultaneously fit plasma levels for both TLP and its metabolite. This suggest that for TLP in humans, (i) N-acetylation represents only a relatively small fraction of its total elimination (about one-fourth in fast acetylators and much less in slow acetylators), (ii) acetylation is about eight-twelve times faster in fast and three-six times faster in intermediate acetylators than in slow acetylators, and (iii) the N-acetyl metabolite is eliminated faster than the parent TLP.

Original languageEnglish
Pages (from-to)125-134
Number of pages10
JournalPharmazie
Volume61
Issue number2
Publication statusPublished - Feb 2006

Fingerprint

GYKI 53405
Acetylation
Metabolites
Polymorphism
Metabolism
Plasmas
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Benzodiazepines
Anticonvulsants
Isoenzymes
Healthy Volunteers
Genotype
Phenotype

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science

Cite this

Influence of the N-acetylation polymorphism on the metabolism of talampanel : An investigation in fasted and fed subjects genotyped for NAT2 variants. / Buchwald, Peter; Juhász, A.; Bell, C.; Pátfalusi, M.; Kovács, P.; Hochhaus, G.; Howes, J.; Bodor, N.

In: Pharmazie, Vol. 61, No. 2, 02.2006, p. 125-134.

Research output: Contribution to journalArticle

Buchwald, P, Juhász, A, Bell, C, Pátfalusi, M, Kovács, P, Hochhaus, G, Howes, J & Bodor, N 2006, 'Influence of the N-acetylation polymorphism on the metabolism of talampanel: An investigation in fasted and fed subjects genotyped for NAT2 variants', Pharmazie, vol. 61, no. 2, pp. 125-134.
Buchwald, Peter ; Juhász, A. ; Bell, C. ; Pátfalusi, M. ; Kovács, P. ; Hochhaus, G. ; Howes, J. ; Bodor, N. / Influence of the N-acetylation polymorphism on the metabolism of talampanel : An investigation in fasted and fed subjects genotyped for NAT2 variants. In: Pharmazie. 2006 ; Vol. 61, No. 2. pp. 125-134.
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