title: The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients.
abstract: CYP2C19 converts the tricyclic antidepressant imipramine to its active metabolite desipramine, which is subsequently inactivated by CYP2D6. The novel CYP2C19*17 allele causes ultrarapid metabolism of CYP2C19 substrates. We genotyped 178 depressed patients on imipramine for CYP2C19*17, and measured steady-state imipramine and desipramine plasma concentrations. Mean dose-corrected imipramine plasma concentration was significantly dependent on CYP2C19 genotype (Kruskal-Wallis test, P=0.01), with circa 30% lower levels in CYP2C19*17/*17 individuals compared with CYP2C19*1/*1 (wild-type) patients. The mean dose-corrected imipramine+desipramine plasma concentrations and imipramine/desipramine ratios were not significantly different between genotype subgroups (Kruskal-Wallis tests, P>or=0.12). In a multivariate analysis, we found a significant, but limited effect (P=0.035, eta(2)=0.031) of the CYP2C19*17 genotype on imipramine+desipramine concentrations. Although the CYP2C19*17 allele is associated with a significantly increased metabolism of imipramine, CYP2C19*17 genotyping will, in our view, not importantly contribute to dose management of patients on imipramine therapy guided by imipramine+desipramine plasma concentrations.
authors.affiliation: Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: P W
authors.initials: PW
authors.lastname: Schenk
authors.forename: M
authors.initials: M
authors.lastname: van Vliet
authors.forename: R A A
authors.initials: RA
authors.lastname: Mathot
authors.forename: T
authors.initials: T
authors.lastname: van Gelder
authors.forename: A G
authors.initials: AG
authors.lastname: Vulto
authors.forename: M A C
authors.initials: MA
authors.lastname: van Fessem
authors.forename: S
authors.initials: S
authors.lastname: Verploegh-Van Rij
authors.forename: J
authors.initials: J
authors.lastname: Lindemans
authors.forename: J A
authors.initials: JA
authors.lastname: Bruijn
authors.forename: R H N
authors.initials: RH
authors.lastname: van Schaik
mesh_terms: D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000097:blood* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D003863:Depression / Q000188:drug therapy* / Q000235:genetics; D003891:Desipramine / Q000097:blood; D005838:Genotype; D006801:Humans; D007099:Imipramine / Q000097:blood* / Q000627:therapeutic use; D008875:Middle Aged; D015999:Multivariate Analysis
chemical_list: D000929:Antidepressive Agents, Tricyclic; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D007099:Imipramine; D003891:Desipramine