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 language | English |
|---|---|
| Pages (from-to) | 377-400 |
| Number of pages | 24 |
| Journal | Journal of Pharmacokinetics and Pharmacodynamics |
| Volume | 32 |
| Issue number | 3-4 |
| DOIs | |
| State | Published - Aug 1 2005 |
| Externally published | Yes |
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Keywords
- 2,3-benzodiazepine
- AMPA antagonist
- N-acetylation
- Polymorphism
ASJC Scopus subject areas
- Pharmacology
- Catalysis
Cite this
Unified pharmacogenetics-based parent-metabolite pharmacokinetic model incorporating acetylation polymorphism for talampanel in humans. / Buchwald, Peter; Juhász, Attila; Bell, Cynthia; Pátfalusi, Márta; Howes, John; Bodor, Nicholas.
In: Journal of Pharmacokinetics and Pharmacodynamics, Vol. 32, No. 3-4, 01.08.2005, p. 377-400.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Unified pharmacogenetics-based parent-metabolite pharmacokinetic model incorporating acetylation polymorphism for talampanel in humans
AU - Buchwald, Peter
AU - Juhász, Attila
AU - Bell, Cynthia
AU - Pátfalusi, Márta
AU - Howes, John
AU - Bodor, Nicholas
PY - 2005/8/1
Y1 - 2005/8/1
N2 - 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.
AB - 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.
KW - 2,3-benzodiazepine
KW - AMPA antagonist
KW - N-acetylation
KW - Polymorphism
UR - http://www.scopus.com/inward/record.url?scp=28444484289&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28444484289&partnerID=8YFLogxK
U2 - 10.1007/s10928-005-0001-y
DO - 10.1007/s10928-005-0001-y
M3 - Article
C2 - 16320099
AN - SCOPUS:28444484289
VL - 32
SP - 377
EP - 400
JO - Journal of Pharmacokinetics and Pharmacodynamics
JF - Journal of Pharmacokinetics and Pharmacodynamics
SN - 1567-567X
IS - 3-4
ER -