title: Unified pharmacogenetics-based parent-metabolite pharmacokinetic model incorporating acetylation polymorphism for talampanel in humans.
abstract: The N-acetylation of the noncompetitive AMPA antagonist talampanel (TLP) represents a route of varying significance in various species. For a detailed analysis in humans, plasma concentrations of TLP and its N-acetyl metabolite (NAc-TLP) were measured for up to 48 h after administration of a single oral dose of 75 mg in 28 healthy volunteers following genotyping for the N-acetyltansferase NAT2 isozymes (alleles NAT2*4, *5, *6, and *7). Unified parent-metabolite pharmacokinetic (PK) models that allowed three different rates of acetylation were used to simultaneously fit plasma levels for both the parent drug and its metabolite following genotype-based classification as slow, intermediate, or fast acetylator. A perfect correspondence was found between the phenotype inferred from genotyping and the phenotype determined by using plasma metabolite-to-parent molar ratios indicating that this route of metabolism is indeed mediated by NAT2. Linear parent-metabolite PK models (first-order input, first-order elimination through two parallel routes one of which is through a metabolite with polymorphic rate of formation) gave adequate and sufficiently consistent fit. Parameters obtained suggest that for TLP in humans, N-acetylation represents only about 1/4th of the total elimination even in true (*4/*4 homozygous) fast acetylators, acetylation is about 8-12 times faster in fast and 3-6 times faster in intermediate acetylators than in slow acetylators, and the N-acetyl metabolite is eliminated faster than the parent drug. Such PK models can provide quantitative estimates of relative in vivo metabolism rates for routes catalyzed by functionally polymorphic enzymes.
authors.affiliation: IVAX Research, Inc., 4400 Biscayne Boulevard, Miami, FL 33137, USA. Peter_Buchwald@ivax.com
authors.forename: Peter
authors.initials: P
authors.lastname: Buchwald
authors.forename: Attila
authors.initials: A
authors.lastname: Juhász
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bell
authors.forename: Márta
authors.initials: M
authors.lastname: Pátfalusi
authors.forename: John
authors.initials: J
authors.lastname: Howes
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bodor
mesh_terms: D000107:Acetylation; D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010641:Phenotype; D011110:Polymorphism, Genetic; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*
chemical_list: D014151:Anti-Anxiety Agents; D018091:Receptors, AMPA; D001569:Benzodiazepines; C085266:talampanel; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human