title: Influence of the N-acetylation polymorphism on the metabolism of talampanel: an investigation in fasted and fed subjects genotyped for NAT2 variants.
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.
authors.affiliation: IVAX Research, Inc., 4400 Biscayne Boulevard, Miami, FL 33137, USA. Peter_Buchwald@ivax.com
authors.forename: P
authors.initials: P
authors.lastname: Buchwald
authors.forename: A
authors.initials: A
authors.lastname: Juhász
authors.forename: C
authors.initials: C
authors.lastname: Bell
authors.forename: M
authors.initials: M
authors.lastname: Pátfalusi
authors.forename: P
authors.initials: P
authors.lastname: Kovács
authors.forename: G
authors.initials: G
authors.lastname: Hochhaus
authors.forename: J
authors.initials: J
authors.lastname: Howes
authors.forename: N
authors.initials: N
authors.lastname: Bodor
mesh_terms: D000107:Acetylation; D000293:Adolescent; D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001569:Benzodiazepines / Q000378:metabolism* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004247:DNA / Q000235:genetics; D004311:Double-Blind Method; D004435:Eating / Q000502:physiology; D005006:Ethnicity; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism* / Q000493:pharmacokinetics; D005215:Fasting / Q000502:physiology; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D001569:Benzodiazepines; D004247:DNA; C085266:talampanel; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human