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 þ 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 (7s.d.) drug dose requirements were 131 (7109), 155 (770), 217 (795), 245 (7125), 326 (7213), and 509 (7292) 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 þ 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.

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 ¼ 0.01), with circa 30% lower levels in CYP2C19*17/*17 individuals compared with CYP2C19*1/*1 (wild-type) patients. The mean dosecorrected imipramine þ desipramine plasma concentrations and imipramine/desipramine ratios were not significantly different between genotype subgroups (Kruskal-Wallis tests, PX0.12). In a multivariate analysis, we found a significant, but limited effect (P ¼ 0.035, Z 2 ¼ 0.031) of the CYP2C19*17 genotype on imipramine þ 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 þ desipramine plasma concentrations.

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Background Resistance to anti‐estrogens is a major problem in breast cancer treatment. The anti‐estrogen tamoxifen is metabolized by cytochrome P450 enzymes. Genetic polymorphisms in these enzymes may alter tamoxifen metabolism and determine response to therapy. Methods Genomic DNA from 248 retrospectively collected estrogen receptor positive primary breast tumor specimens from patients with advanced disease were analysed for CYP2D6, 2B6, 2C9, 2C19 and 3A5 variant alleles. Results were compared to patient and tumor characteristics, outcome of response and time to tumor progression. Results No relation between patient or tumor characteristics and CYP450 genotype was observed, nor did CYP3A5, 2B6, 2C9 or 2D6 genotype correlate with treatment outcome. However, the CYP2C19*1/*1 genotype was significantly associated with a shorter time to tumor progression (hazard ratio 0.64; 95% C.I. 0.47–0.87; p=0.004). Conclusions Our data suggest that the duration of response to tamoxifen therapy is dependent on CYP2C19 genotype. Further studies are needed to investigate whether inhibition of CYP2C19 activity may result in a longer response to tamoxifen. Clinical Pharmacology & Therapeutics (2005) 77, P23–P23; doi: