Unified pharmacogenetics-based parent-metabolite pharmacokinetic model incorporating acetylation polymorphism for talampanel in humans

Peter Buchwald, Attila Juhász, Cynthia Bell, Márta Pátfalusi, John Howes, Nicholas Bodor

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)377-400
Number of pages24
JournalJournal of Pharmacokinetics and Pharmacodynamics
Volume32
Issue number3-4
DOIs
StatePublished - Aug 1 2005

Keywords

  • 2,3-benzodiazepine
  • AMPA antagonist
  • N-acetylation
  • Polymorphism

ASJC Scopus subject areas

  • Pharmacology
  • Catalysis

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