The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients.
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.
Schenk
P W
PW
Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands.
van Vliet
M
M
Mathot
R A A
RA
van Gelder
T
T
Vulto
A G
AG
van Fessem
M A C
MA
Verploegh-Van Rij
S
S
Lindemans
J
J
Bruijn
J A
JA
van Schaik
R H N
RH
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
D000929:Antidepressive Agents, Tricyclic; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D007099:Imipramine; D003891:Desipramine