Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients

Schenk, Paul W.; Fessem, M A C van; Rij, S Verploegh-Van; Mathôt, Ron A. A.; Gelder, Teun van; Vulto, Arnold G.; Vliet, Martin van; Lindemans, Jan; Bruijn, Jan A.; Schaik, Ron H.N. van

doi:10.1038/sj.mp.4002057

Cited by 41 publications

(25 citation statements)

References 46 publications

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“…24 Ethnicity was not explicitly recorded, but the vast majority (495%) of patients were Caucasians. The Ethics Committee of the Erasmus MC approved the protocol, the study was carried out according to the principles of the Declaration of Helsinki, and patients provided written informed consent.…”

Section: Patientsmentioning

confidence: 99%

“…Imipramine and desipramine plasma concentrations were measured at the Department of Hospital Pharmacy on a regular basis, according to a routine procedure by using HPLC with ultraviolet detection at 220 nm as described. 24 The imipramine dose was adjusted based on a predefined imipramine þ desipramine target plasma concentration of 200-300 mg l À1 . 7 Given the elimination half-life values of 8-20 and 12-76 h for imipramine and desipramine, 25 respectively, treatment with an unchanged dose of imipramine for at least 12 consecutive days (4 Â 3 days, or four elimination half-lives for the compound and phenotype with longest elimination half-life) was chosen as to define the steady state.…”

Section: Clinical Studymentioning

confidence: 99%

“…For each individual patient, a median value of all imipramine and imipramine þ desipramine plasma levels at steady state, and all molar imipramine/desipramine ratios at steady state was calculated, using molecular masses of 280.4 and 266.3 g mol À1 for imipramine and desipramine, respectively. 24,26 The median individual steady-state values were then used for all (sub)group analyses, that is, medians were used for each individual, whereas mean values were only used for observations applying to (sub)groups of patients.…”

Section: Clinical Studymentioning

confidence: 99%

“…CYP2C19*2 and CYP2D6 *1-*6, *9, *10 and *41 genotypes, and CYP2D6 gene duplication, were assessed by PCR-restriction fragment length polymorphism analysis and conventional PCR as previously described. 24 CYP2D6 alleles were designated according to the Human Cytochrome P450 Allele Nomenclature Committee website. 11 Individuals with two CYP2D6 null alleles (*3, *4, *5 or *6; n ¼ 9, corresponding to 5% of the patient group) and subjects showing gene duplication resulting in three or more active alleles (n ¼ 11, 6%) were classified as CYP2D6 poor and ultrarapid metabolizers, respectively.…”

Section: Genotypingmentioning

confidence: 99%

“…Variables sex, body weight, number of CYP2C19*17 alleles and number of active CYP2D6 alleles (semiquantitative functional gene dose as previously described 3,24 ) were considered to be of potential interest for the prediction of mean dose-corrected imipramine plasma level, imipramine þ desipramine plasma concentration and molar imipramine/ desipramine ratio using a linear regression model. When univariately analyzed, all variables significantly contributed to the prediction of imipramine plasma concentration per dose unit (Pp0.026).…”

Section: Univariate and Multivariate Analysismentioning

confidence: 99%

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The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

et al. 2009

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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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Section: Patientsmentioning

confidence: 99%

Section: Clinical Studymentioning

confidence: 99%

Section: Clinical Studymentioning

confidence: 99%

Section: Genotypingmentioning

confidence: 99%

Section: Univariate and Multivariate Analysismentioning

confidence: 99%

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The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

et al. 2009

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Flexible and Scalable Full-Length CYP2D6 Long Amplicon PacBio Sequencing

et al. 2017

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Cytochrome P450 2D6 (CYP2D6) is among the most important genes involved in drug metabolism. Specific variants are associated with changes in the enzyme's amount and activity. Multiple technologies exist to determine these variants, like the AmpliChip CYP450 test, Taqman qPCR, or Second‐Generation Sequencing, however, sequence homology between cytochrome P450 genes and pseudogene CYP2D7 impairs reliable CYP2D6 genotyping, and variant phasing cannot accurately be determined using these assays. To circumvent this, we sequenced CYP2D6 using the Pacific Biosciences RSII and obtained high‐quality, full‐length, phased CYP2D6 sequences, enabling accurate variant calling and haplotyping of the entire gene‐locus including exonic, intronic, and upstream and downstream regions. Unphased diplotypes (Roche AmpliChip CYP450 test) were confirmed for 24 of the 25 samples, including gene duplications. Cases with gene deletions required additional specific assays to resolve. In total, 61 unique variants were detected, including variants that had not previously been associated with specific haplotypes. To further aid genomic analysis using standard reference sequences, we have established an LOVD‐powered CYP2D6 gene‐variant database, and added all reference haplotypes and data reported here. We conclude that our CYP2D6 genotyping approach produces reliable CYP2D6 diplotypes and reveals information about additional variants, including phasing and copy‐number variation.

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