Effects of 24 CYP2D6 Variants Found in the Chinese Population on the Metabolism of Risperidone

Wang, Zhenhe; Zhan, Yun-Yun; Li, Yunxuan; Yang, Chengcheng; Cai, Jie; Dai, Da‐Peng; Hu, Guo-Xin; Cai, Jian‐Ping

doi:10.1159/000441007

Cited by 9 publications

(10 citation statements)

References 30 publications

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“…Consequently, our results showed notably decreased intrinsic clearance of the 2 variants, 39.70% for CYP2D6 * 2 and 5.22% for CYP2D6 * 10 relative to wildtype. This was consistent with the investigation of dextromethorphan, bufuralol, venlafaxine, atomoxetine and risperidone in our laboratory [7,[27][28][29].…”

Section: Discussionsupporting

confidence: 91%

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Effects of 22 CYP2D6 Genetic Variations Newly Identified in Chinese Population on Olanzapine Metabolism in vitro

Zhou

Gu²,

Chen³

et al. 2016

Pharmacology

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The objective of this study was to assess the catalytic activity of 22 novel CYP2D6 allelic variants (2D6*87-*98, R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C and R497C) to olanzapine in vitro. Their protein products expressed in Spodoptera frugiperda 21 (Sf21) insect cells were incubated with olanzapine 100-2,000 μmol/l for 30 min. The kinetic parameters of K_m, V_max and intrinsic clearance were determined by 2-hydroxymethylolanzapine, the metabolite of olanzapine mediated by CYP2D6, using ultra-performance liquid chromatography tandem mass spectrometry. Results showed that the kinetic parameters of 2 alleles, CYP2D6*92 and 2D6*96, could not be detected; 17 allelic variants, CYP2D6*87-*88, 2D6*90-*91, 2D6*93-*95, 2D6*97, R25Q, F164L, E215K, F219S, V327M, V342M, R344Q, R440C and R497C, significantly reduced the intrinsic clearance of olanzapine; 2 variants, CYP2D6*89 and 2D6*98, increased the intrinsic clearance of olanzapine; no difference was found in intrinsic clearance of D336N. Furthermore, 6 alleles, CYP2D6*87, 2D6*88, 2D6*91, 2D6*93, 2D6*97 and R497C, exhibited higher K_m values in a range of 120.80-217.56% relative to wild-type CYP2D6*1. The research demonstrated the metabolic phenotype of the 22 novel CYP2D6 variants for olanzapine that were different from probe drugs we used previously and might provide beneficial information to the personalized medicine of olanzapine.

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Section: Discussionsupporting

confidence: 91%

“…In our laboratory, CYP2D6 * 2 and CYP2D6 * 10 were used as controls for decreased function and exhibited 54.3-1.3% relative clearance [7,[27][28][29] (and this study). We supposed that alleles with the relative clearance less or close to CYP2D6 * 2 are more likely to indicate pharmacokinetic changes in vivo.…”

Section: Discussionmentioning

confidence: 99%

Effects of 22 CYP2D6 Genetic Variations Newly Identified in Chinese Population on Olanzapine Metabolism in vitro

Zhou

Gu²,

Chen³

et al. 2016

Pharmacology

Self Cite

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“…The latter amino acid substitution has been shown to cause protein instability and reduced substrate affinity (Wang et al, 1999). As reported by previous studies, CYP2D6.10 yields 1.34%-4.57% of the efficiency of CYP2D6*1 toward bufuralol (1.34%), propranolol (1.41%), risperidone (2.01%), venlafaxine (2.90%), and dextromethorphan (4.57%) in vitro (Liang et al, 2015;Wang et al, 2015;Cai et al, 2016;Zhan et al, 2016). In our study, CYP2D6.10 had a decreased V max (8.71%), an increased K m (3.62-fold), and a significantly decreased intrinsic clearance (4.07%) of nebivolol compared with CYP2D6.1.…”

Section: Resultssupporting

confidence: 65%

“…In a study of dextromethorphan and bufuralol, Dai et al (2015) suggested that L142S could impair enzymatic activity to some extent, resulting in extremely decreased intrinsic clearance values (,20%) of CYP2D6.1. In other studies, CYP2D6.89 exhibited markedly different catalytic activity toward venlafaxine (71.1%), methadone (74.62%), risperidone (87.56%), and atomoxetine (102.6%) compared with CYP2D6.1 (Wang et al, 2015;Liang et al, 2016;Su et al, 2016;Zhan et al, 2016). Our data revealed that this variant showed no significant difference compared with the wild type but showed a trend of substrate inhibition (Fig.…”

Section: Resultssupporting

confidence: 48%

Evaluation of 24 CYP2D6 Variants on the Metabolism of Nebivolol In Vitro

Lan

Dai

et al. 2016

Drug Metabolism and Disposition

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CYP2D6 is an important cytochrome P450 (P450) enzyme that metabolizes approximately 25% of therapeutic drugs. Its genetic polymorphisms may significantly influence the pharmacokinetics and pharmacodynamics of clinically used drugs. Studying the effects of CYP2D6 on drug metabolism can help reduce adverse drug reactions and therapeutic failure to some extent. This study aimed to investigate the role of CYP2D6 in nebivolol metabolism by evaluating the effect of 24 CYP2D6 variants on the metabolism of nebivolol in vitro. CYP2D6 variants expressed by insect cell systems were incubated with 0.1-80 μM nebivolol for 30 minutes at 37°C and the reaction was terminated by cooling to -80°C immediately. An ultra-performance liquid chromatography-tandem mass spectrometry system was used to analyze nebivolol and its metabolite 4-hydroxy nebivolol. Compared with CYP2D6.1, the intrinsic clearance values of most variants were significantly altered, and most of these variants exhibited either reduced V and/or increased K values. Variant R440C showed much higher intrinsic clearance than the wild type (219.08%). Five variants (CYP2D6.88, CYP2D6.89, R344Q, V342M, and D336N) exhibited no difference from the wild type. CYP2D6.92 and CYP2D6.96 displayed weak or no activity, whereas the intrinsic clearance values of the remaining 16 variants were significantly reduced to various degrees (ranging from 4.07% to 71%). As the first report of 24 CYP2D6 alleles for nebivolol metabolism, these results are valuable to interpreting in vivo studies and may also serve as a reference for rational clinical administration.

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“…We validate the genotype-based activity predictor and star allele classifier using in vitro data from literature. We identified two sets of studies to use for validation: (1) a functional characterization of 49 CYP2D6 star alleles performed using three substrates, and (2) eight in vitro studies of eleven CYP2D6 star alleles discovered in Han Chinese subjects using ten substrates [45][46][47][48][49][50][51][52][53][54] . We exclude fourteen star alleles which were found in our training data, and evaluate on measurements for 46 star alleles that were not in our training data.…”

Section: Literature Validationmentioning

confidence: 99%

Transfer learning enables prediction ofCYP2D6haplotype function

McInnes

Dalton

Sangkuhl

et al. 2019

Preprint

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A major limitation of phenotype prediction in genetics is the ability to model the complexities of genetic variation when sample sizes are small. This is especially true in pharmacogenetics, ahighly translational yet data-limited subfield of genetics. Drug metabolism is a critical facet of pharmacogenetics and can have consequences for drug safety and efficacy. CYP2D6 is an 1 important enzyme, metabolizing more than 25% of clinically used drugs. It is highly polymorphic which leads to a heterogeneous response to drugs among the population.We presentHubble2D6, a set of deep learning models for predicting metabolic activity of CYP2D6 genotype and predicting functional classification of CYP2D6 haplotypes. We train our models on 249 samples, addressing data scarcity by pretraining on simulated data, weakly supervised learning, and using a functional representation of genetic variants. We validate our models using in vitro data for haplotypes previously unseen by the model and explain 38% of the variance with the genotype-based activity predictor and predict haplotype function with an AUC of 0.85. We demonstrate a procedure to build a computational model of a complex gene using primarily simulated and unlabeled data which can then be used to make functional predictions about novel genetic variation, and present a model that may be of clinical significance for an important application of genetics.

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Effects of 24 CYP2D6 Variants Found in the Chinese Population on the Metabolism of Risperidone

Cited by 9 publications

References 30 publications

Effects of 22 <b><i>CYP2D6</i></b> Genetic Variations Newly Identified in Chinese Population on Olanzapine Metabolism in vitro

Effects of 22 <b><i>CYP2D6</i></b> Genetic Variations Newly Identified in Chinese Population on Olanzapine Metabolism in vitro

Evaluation of 24 CYP2D6 Variants on the Metabolism of Nebivolol In Vitro

Transfer learning enables prediction ofCYP2D6haplotype function

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