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 dosecorrected 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, n2=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.

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Keywords Cytochromes, Depression, Genetic polymorphism, Imipramine, Pharmacogenetics, Tricyclic antidepressive agents
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Journal The Pharmacogenomics Journal
Schenk, P.W, van Vliet, M.H, Mathot, R.A, van Gelder, T, Vulto, A.G, van Fessem, M.A, … van Schaik, R.H.N. (2010). The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients. The Pharmacogenomics Journal, 10(3), 219–225. doi:10.1038/tpj.2009.50