The CYP2C1917 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

• Published in: The pharmacogenomics journal Vol. 10; no. 3; pp. 219 - 225
• Main Authors: Schenk, P W, van Vliet, M, Mathot, R A A, van Gelder, T, Vulto, A G, van Fessem, M A C, Verploegh-Van Rij, S, Lindemans, J, Bruijn, J A, van Schaik, R H N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2010; Nature Publishing Group
• Subjects: Adult; Alleles; Analysis; Antidepressants; Antidepressive Agents, Tricyclic - blood; Antidepressive Agents, Tricyclic - therapeutic use; Aryl Hydrocarbon Hydroxylases - genetics; Biomedical and Life Sciences; Biomedicine; CYP2D6 protein; Cytochrome P-450; Cytochrome P-450 CYP2C19; Cytochrome P450; Depression - drug therapy; Depression - genetics; Depression, Mental; Desipramine; Desipramine - blood; Dosage and administration; Drug therapy; Gene Expression; Genetic aspects; Genotype; Genotype & phenotype; Genotypes; Genotyping; Human Genetics; Humans; Imipramine; Imipramine - blood; Imipramine - therapeutic use; Metabolism; Metabolites; Middle Aged; Multivariate Analysis; Oncology; original-article; Pharmacogenetics; Pharmacotherapy; Physiological aspects; Plasma; Psychopharmacology; Netherlands; depression; genetic polymorphism; tricyclic antidepressive agents; pharmacogenetics; imipramine; cytochromes
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/tpj.2009.50

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 ⩾0.12). In a multivariate analysis, we found a significant, but limited effect ( P =0.035, η 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.