Influence of the N-acetylation polymorphism on the metabolism of talampanel: an investigation in fasted and fed subjects genotyped for NAT2 variants.

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.

RCT Entities:   Population Interventions Outcomes