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

Abstract

Amitriptyline is a tricyclic antidepressant that is metabolized mainly by CYP2C19 and CYP2D6 enzymes. Higher plasma levels of amitriptyline and its active metabolite, nortriptyline, are associated with an increased risk of adverse events including anticholinergic effects. The aim of this study was to evaluate the effects of CYP2C19 and CYP2D6 genetic polymorphisms on amitriptyline and nortriptyline pharmacokinetics. Twenty‐four Korean healthy adult male volunteers were enrolled in the study after stratification by their CYP2C19 and CYP2D6 genotypes. Serial blood draws for pharmacokinetic analysis were made after a single oral 25‐mg dose of amitriptyline was administered. Plasma amitriptyline and nortriptyline concentrations were measured by a validated liquid chromatography with tandem mass spectrometry. Population pharmacokinetic modeling analysis was conducted using NONMEM, which evaluated the effects of CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. The biotransformation of amitriptyline into nortriptyline was significantly different between subjects with the CYP2C19*2/*2, *2/*3, and *3/*3 genotypes and those with the other genotypes, with an estimated metabolic clearance of 17 and 61.5 L/h, respectively. Clearance of amitriptyline through pathways other than biotransformation into nortriptyline was estimated as 18.8 and 30.6 L/h for subjects with the CYP2D6*10/*10 and *10/*5 genotypes and those with the other genotypes, respectively. This study demonstrated a quantitative effect of the CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. Production of nortriptyline from amitriptyline was associated with CYP2C19 genotypes, and clearance of amitriptyline through pathways other than biotransformation into nortriptyline was associated with CYP2D6 genotypes. These observations may be useful in developing individualized, optimal therapy with amitriptyline.

Therapy Response Prediction in Major Depressive Disorder: Current and Novel Genomic Markers Influencing Pharmacokinetics and Pharmacodynamics

“…The alleles CYP2C19*2 and CYP2C19*3 code for an inactive enzyme and are the most common reason for the occurrence of IM (heterozygous) or PM phenotypes (homozygous) of CYP2C19 in different populations [46]. PMs show a decreased metabolism of amitriptyline and a higher plasma concentration of the drug in healthy individuals and patients [23,27,39]. Similar observations have been reported for imipramine [47] or clomipramine [33,48].…”

“…Following a glucuronidation, TCAs are excreted in the urine [22]. The polymorphic expressed enzymes such as CYP2D6, CYP2C19, CYP2C9 (besides CYP3A4) and to a lesser extent CYP1A2, are the main players in the metabolism of TCAs [23][24][25][26][27]. SNPs in genes encoding CYP enzymes have been well studied regarding their impact on pharmacokinetics, therapeutic safety and efficacy of TCAs.…”

Influence of metabolic state and body composition on the action of pharmacological treatment of migraine

“…The plasma half-life ranges from 10-28 h [ 72 , 73 ]. Amitriptyline metabolism involves complex pathways, including demethylation mediated by CYP2C19 and hydroxylation mediated by CYP2D6, along with other isozymes like CYP3A4, CYP1A2, and CYP2C9 [ 74 , 75 ]. Genetic polymorphisms can impact its metabolism, resulting in elevated plasma levels [ 76 ].…”

Integrated Module of Multidimensional Omics for Peripheral Biomarkers (iMORE) in patients with major depressive disorder: rationale and design of a prospective multicentre cohort study

“…Antidepressants are largely metabolised by cytochrome P450 (CYP450) enzymes family (CYP2C9, CYP2C19, CYP2D6, etc), while related genetic variations substantially modify the pharmacokinetics leading to individual differences. [27][28][29] Commercial kits of pharmacogenomics have been used in some clinical trials to aid the drug selection with improved outcomes. 30 31 More complicated factors, however, need to be considered because metabolic phenotypes are influenced not only by genotype but also by environmental factors, such as age, nutrition, comorbidity and intestinal microecology.…”

“…As tools of prediction in genomics,25 26 pharmacogenomics is widely used to evaluate drug–gene interactions and impacts on efficacy by genetic polymorphism. Antidepressants are largely metabolised by cytochrome P450 (CYP450) enzymes family (CYP2C9, CYP2C19, CYP2D6, etc), while related genetic variations substantially modify the pharmacokinetics leading to individual differences 27–29. Commercial kits of pharmacogenomics have been used in some clinical trials to aid the drug selection with improved outcomes 30 31.…”