Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients.
The inactivation and clearance of the tricyclic antidepressant imipramine is dependent on CYP2D6 activity. First, CYP2C19 converts imipramine into the active metabolite desipramine, which is then inactivated by CYP2D6. This retrospective single center study aimed to prove whether CYP2C19 and ample CYP2D6 genotyping (taking into consideration four null alleles and three decreased-activity alleles) could be used to predict imipramine and desipramine plasma concentrations in depressed patients, and whether genotype-based drug dose recommendations might assist in the early management of imipramine pharmacotherapy. In 181 subjects with major depressive disorder, drug doses were recorded, imipramine and desipramine plasma concentrations were monitored and CYP2C19 (*2) and CYP2D6 genotype (*3, *4, *5, *6, *9, *10, *41 and gene duplication) were obtained, yielding graded allele-specific CYP2D6 patient groups. Desipramine and imipramine+desipramine plasma concentration per drug dose unit, imipramine dose at steady state, and imipramine dose requirement significantly depended on CYP2D6 genotype (Kruskal-Wallis test, P<0.0001). Mean (+/-s.d.) drug dose requirements were 131 (+/-109), 155 (+/-70), 217 (+/-95), 245 (+/-125), 326 (+/-213), and 509 (+/-292) mg imipramine/day in carriers of 0, 0.5, 1, 1.5, 2, and >2 active CYP2D6 genes, respectively. Our protocol for CYP2D6 genotyping will thus importantly aid in the prediction of imipramine metabolism, allowing for the use of an adjusted starting dose and faster achievement of predefined imipramine+desipramine plasma levels in all genetic patient subgroups. Therefore, therapeutic efficacy and efficiency may be improved, the number of adverse drug reactions decreased, and hospital stay reduced.
Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
P W
PW
Schenk
M A C
MA
van Fessem
S
S
Verploegh-Van Rij
R A A
RA
Mathot
T
T
van Gelder
A G
AG
Vulto
M
M
van Vliet
J
J
Lindemans
J A
JA
Bruijn
R H N
RH
van Schaik
D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000097:blood* / Q000187:drug effects / Q000235:genetics*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D003891:Desipramine / Q000097:blood / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005838:Genotype; D006801:Humans; D007099:Imipramine / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012189:Retrospective Studies
D000929:Antidepressive Agents, Tricyclic; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D007099:Imipramine; D003891:Desipramine