A Study on CYP2C19 and CYP2D6 Polymorphic Effects on Pharmacokinetics and Pharmacodynamics of Amitriptyline in Healthy Koreans

Abstract

We performed a double‐blinded, genotype‐based stratification study to explore the pharmacokinetics and pharmacodynamics of amitriptyline according to CYP2C19 and CYP2D6 genotype in Korean subjects. Twenty‐four healthy adults were grouped by genotype of CYP2C19 and CYP2D6. After a single dose of 25 mg of amitriptyline, blood samples were collected and anticholinergic effects were measured. The extent of N‐demethylation of amitriptyline significantly decreased in subjects carrying two nonfunctional alleles of CYP2C19. The extent of hydroxylation of amitriptyline or nortriptyline was significantly reduced in subjects carrying two CYP2D6 decreased functional alleles compared with those with no or one decreased functional allele. The overall metabolic pathway of amitriptyline was more likely to be dominated by CYP2C19 than CYP2D6. The gene variations of CYP2C19 and CYP2D6 did not change the pharmacodynamic effect. The findings of this study will provide useful information on individualized drug treatment with amitriptyline considering both CYP2D6 and CYP2C19 gene variations.

Quantitative Modeling Analysis Demonstrates the Impact of CYP2C19 and CYP2D6 Genetic Polymorphisms on the Pharmacokinetics of Amitriptyline and Its Metabolite, Nortriptyline

“…The CYP2D6 allele *10, the most common functional variant in East Asians, is associated with reduced enzymatic activity resulting from the formation of an unstable enzyme. As many as 50% of Koreans carry this allele, compared with 2% of whites . This difference might be one of the reasons why the median CYP2D6 enzyme activity is lower in East Asians with genotypes representing extensive CYP2D6 metabolizers than in white individuals with the genotypes representing extensive CYP2D6 metabolizers .…”

“…Each subject received a single oral dose of 25 mg of amitriptyline (Etravil). Blood for the pharmacokinetic analysis was drawn immediately before the oral administration of amitriptyline (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after administration . The plasma concentrations of amitriptyline and nortriptyline were measured using validated liquid chromatography coupled with tandem mass spectrometry with a few modifications …”

“…Blood for the pharmacokinetic analysis was drawn immediately before the oral administration of amitriptyline (0 hour) and at 0.5, 1, 1.5, 2, 3,4,6,8,12,24,48,72, and 96 hours after administration. 9 The plasma concentrations of amitriptyline and nortriptyline were measured using validated liquid chromatography coupled with tandem mass spectrometry with a few modifications. [11][12][13] *1/*10, *1/*5 *1/*1, *1/*2, *1/*3 6 III *10/*10, *10/*5, *5/*5 *1/*1, *1/*2, *1/*3 6 IV *1/*1, *1/*10, *1/*5, *10/*10, *10/*5, *5/*5 *2/*2, *2/*3, *3/*3 6…”

“…Therefore, recommended doses of amitriptyline should possibly differ based on CYP2D6 and CYP2C19 genotype . Previously, a pharmacokinetic study was conducted in 24 Korean healthy male subjects to investigate the effect of genetic polymorphisms of CYP2C19 and CYP2D6 on the pharmacokinetics of amitriptyline and nortriptyline …”

“…4,5 Previously, a pharmacokinetic study was conducted in 24 Korean healthy male subjects to investigate the effect of genetic polymorphisms of CYP2C19 and CYP2D6 on the pharmacokinetics of amitriptyline and nortriptyline. 9 The aim of this study was to evaluate the pharmacokinetic characteristics of amitriptyline and nortriptyline by modeling analysis and the quantitative effect of CYP2C19 and CYP2D6 genetic polymorphisms on amitriptyline and nortriptyline pharmacokinetics.…”