Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping

Frank, Dorothee; Jaehde, Ulrich; Fuhr, Uwe

doi:10.1007/s00228-006-0250-8

Cited by 147 publications

(141 citation statements)

References 79 publications

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“…Since not all possible genetic variations in CYP2D6 were investigated in our study, misclassification may also arise from the assignment of the *1 allele to individuals who harbor a rare, activity-lowering CYP2D6 mutation. Additionally, CYP2D6 phenotyping by using urinary dextromethorphanbased metabolite ratios may not be the optimal phenotyping tool, because small activity differences cannot be reliably detected [5,6], which in turn, may also lead to misclassifications.…”

Section: Discussionmentioning

confidence: 99%

Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy

Mwinyi

Vokinger

Jetter

et al. 2014

Cancer Chemother Pharmacol

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BACKGROUND Tamoxifen is frequently used for the treatment of hormone receptor positive breast cancer (BC). Mainly CYP2D6 is responsible for the transformation to therapeutically active metabolites, but CYP2C19, CYP2C9 and CYP2B6 also are involved. We investigated the impact of polymorphisms within the genes encoding these CYP enzymes on the relapse-free time (RFT) in patients with BC. METHODS Ninety-nine patients with hormone receptor positive BC, who had undergone adjuvant tamoxifen therapy, were genotyped for seventeen common variants within the genes encoding CYP2D6, CYP2C9, CYP2C19 and CYP2B6 using TaqMan and PCR-RFLP technology. KaplanMeier and Cox regression analyses were performed to elucidate the impact of genetic variants on RFT. Furthermore, CYP2D6 metabolic activity was determined in a subset of 50 patients by assessing dextromethorphan/dextrorphan urinary excretion ratios. CYP2D6 activity was compared to the CYP2D6 allelic combinations to evaluate the predictive value of the CYP2D6 genotyping results on phenotype. RESULTS Although a trend toward longer RFTs in carriers of CYP2D6 allele combinations encoding for extensive and ultrafast metabolizer phenotypes was observed, none of the investigated genetic variants had a statistically significant impact on RFT. The combined analysis of five major CYP2D6 variants was useful for the discrimination between poor and non-poor metabolizers. CONCLUSIONS Comprehensive CYP2D6 genotyping has a good predictive value for CYP2D6 activity.

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Section: Discussionmentioning

confidence: 99%

Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy

Mwinyi

Vokinger

Jetter

et al. 2014

Cancer Chemother Pharmacol

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“…However, depending on the probe drug used to phenotype, differences in exact determination of CYP2D6 enzymatic activity may be observed. 25 Moreover, using therapeutic drugs to define genotype-phenotype association was also shown to be very promising. Indeed, as reported by Steimer et al, 22 for patients receiving amitriptyline, the concentrations of its metabolite nortriptyline were significantly associated to the different genotype combinations within the EM group according to the functional gene dose.…”

Section: Genotype-phenotype Associationmentioning

confidence: 99%

The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction

et al. 2008

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Polymorphisms of the cytochrome P450 2D6 (CYP2D6) gene affecting enzyme activity are involved in interindividual variability in drug efficiency/ toxicity. Four phenotypic groups are found in the general population: ultra rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. The AmpliChip CYP450 test is the first genotyping array allowing simultaneous analysis of 33 CYP2D6 alleles. The main aim of this study was to evaluate the performance of this test in CYP2D6 phenotype prediction. We first verified the AmpliChip CYP450 test genotyping accuracy for five CYP2D6 alleles routinely analysed in our laboratory (alleles 3,4,5,6, Â N; n ¼ 100). Results confirmed those obtained by real-time PCR. Major improvements using the array are the detection of CYP2D6 intermediate alleles and identification of the duplicated alleles. CYP2D6 phenotype was determined by assessing urinary elimination of dextromethorphan and its metabolite dextrorphan and compared to the array prediction (n ¼ 165). Although a low sensitivity of UM prediction by genotyping was observed, phenotype prediction was optimal for PM and satisfying for EM and IM.

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“…This phenotyping approach can be considered targeted "metabolomics." Advantages of this serum-based approach include development of a metabolic curve within several hours compared to the more time-consuming urinary clearance methods [46]. Microdosing allows for administration of small probe drug doses minimizing the possibility of clinical effects from probe drugs as well as decreasing the risk of interaction between the probe drugs themselves [47].…”

Section: Phenotyping To Integrate Complex Pathway Functionmentioning

confidence: 99%

“…Microdosing allows for administration of small probe drug doses minimizing the possibility of clinical effects from probe drugs as well as decreasing the risk of interaction between the probe drugs themselves [47]. Serum measurements are more precise and are not prone to the same pHdependent inaccuracies associated with urinary metabolic ratio studies [46]. Serum testing is ideal for emergency department (ED) phenotyping since many subjects do not spend adequate time in the ED for urinary studies, and many subjects in this venue have co-morbid diseases that may affect urinary studies.…”

Section: Phenotyping To Integrate Complex Pathway Functionmentioning

confidence: 99%

Prediction of Drug Response and Safety in Clinical Practice

2011

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Many clinicians hoped that the completion of the Human Genome Project would result in "individualized drug therapy," i.e., determining the right medication at the right dose 100% of the time based upon the individual's genetics. The pharmacogenomic prediction of drug efficacy and safety has not become a reality due to continuing realization of the complexity dictating the human-drug interaction. New methods of metabolomics, proteomics, and transcriptomics that account for this complexity hold promise for translational researchers hoping to increase drug efficacy and decrease drug toxicity.

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Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping

Cited by 147 publications

References 79 publications

Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy

Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy

The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction

Prediction of Drug Response and Safety in Clinical Practice

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