The CYP2C19(star)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(star)17 allele causes ultrarapid metabolism of CYP2C19 substrates. We genotyped 178 depressed patients on imipramine for CYP2C19(star)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(star)17/(star)17 individuals compared with CYP2C19(star)1/(star)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, eta(2) = 0.031) of the CYP2C19(star)17 genotype on imipramine+desipramine concentrations. Although the CYP2C19(star)17 allele is associated with a significantly increased metabolism of imipramine, CYP2C19(star)17 genotyping will, in our view, not importantly contribute to dose management of patients on imipramine therapy guided by imipramine+desipramine plasma concentrations. The Pharmacogenomics Journal (2010) 10, 219-225; doi:10.1038/tpj.2009.50; published online 3 November 2009