Effect of CYP2D6 variants on venlafaxine metabolism in vitro

Zhan, Yun-Yun; Liang, Bo; Wang, Hao; Wang, Zhenhe; Weng, Qinghua; Dai, Da‐Peng; Cai, Jian‐Ping; Hu, Guoxin

doi:10.3109/00498254.2015.1089364

Cited by 15 publications

(16 citation statements)

References 26 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: 74%

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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: 74%

“…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

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“…In our study, both CYP2D6.92 and CYP2D6.96 had undetectable enzyme activity in gefitinib metabolism, similar to previous reports 19,21,23,24. The reason for this may be because both of these variants were expressed as truncated proteins due to the premature termination in protein translation process, which led to the function loss of enzymatic activity.…”

Section: Discussionsupporting

confidence: 89%

“…Particularly, only one variant CYP2D6.94, with a decrease K m and an increase V max , showed significant increased relative clearance compared with CYP2D6.1, suggesting higher catalytic activity than CYP2D6.1. On the contrary, as reported in other studies, CYP2D6.94 exhibited markedly different decreased catalytic activity toward propranolol (31.37%), nebivolol (58.23%), dextromethorphan (67.03%), venlafaxine (71.9%), and bufuralol (74.96%) in vitro 19,21,23,24. These data suggest that CYP2D6.94 may be reclassified as an ultrarapid metabolizer phenotype for gefitinib.…”

Section: Discussionmentioning

confidence: 49%

Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

Fang

Zheng

et al. 2017

DDDT

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BackgroundCytochrome P450 2D6 (CYP2D6), a member of the CYP450 enzyme super family, is a polymorphic enzyme that metabolizes ~25% of therapeutic drugs. CYP2D6 exhibits significant genetic polymorphisms which might cause adverse effects and therapeutic failures of some drugs.ObjectiveThe purpose of this study was to evaluate the catalytic activities of 22 novel CYP2D6 alleles (CYP2D6*87, *88, *89, *90, *91, *92, *93, *94, *95, *96, *97, *98, R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C, R497C) on the metabolism of gefitinib in vitro.Methods and resultsCYP2D6 variants were incubated with 1–100 μM gefitinib for 60 min at 37°C and the reaction was terminated by cooling to −80°C immediately. Gefitinib and its metabolite O-desmethyl gefitinib were analyzed by an ultra-performance liquid chromatography-tandem mass spectrometry system. Compared to CYP2D6.1, most CYP2D6 variants exhibited significantly decreased relative clearance values (from 3.11% to 79.35%), whereas CYP2D6.92 and CYP2D6.96 displayed no detectable enzyme activity. Only CYP2D6.94 exhibited a markedly increased intrinsic clearance value, and eight variants (CYP2D6.88, CYP2D6.89, CYP2D6.91, CYP2D6.97, V342M, R344Q, F219S, and F164L) showed no significant difference. In addition, 23 CYP2D6 allelic isoforms exhibited substrate inhibition trend toward gefitinib.ConclusionAs the first study of all the aforementioned alleles for gefitinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism of gefitinib, and may also offer a reference for personalized treatment with gefitinib in clinical settings.

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“…Seventeen allelic variants exhibited decreased Vmax or increased Km that lead to lower intrinsic clearance values than CYP2D6.1, of which the percentage varied from 4.3 to 87.19%. This was different from our previous in vitro metabolic ability assessment results on bufuralol [13], dextromethorphan [13], and venlafaxine [14]. Seventeen tested CYP2D6 allelic isoforms exhibited substrate inhibition trend toward atomoxetine; the wild type was included, whereas CYP2D6.V327M, CYP2D6.91, CYP2D6.F219S, CYP2D6.95, and CYP2D6.E215K did not.…”

Section: Resultsmentioning

confidence: 81%

Effect of 24 Cytochrome P450 2D6 Variants Found in the Chinese Population on Atomoxetine Metabolism in vitro

Liang

Zhan²,

Wang³

et al. 2015

Pharmacology

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Objective: The aim of this article was to assess the catalytic activities of 24 cytochrome P450 2D6 (CYP2D6) variants found in the Chinese population toward atomoxetine in vitro as well as CYP2D6.1. Methods: In this study, the co-expression enzyme of human recombinant CYPOR, CYPb5, and CYP2D6.1 or other CYP2D6 variants with the baculovirus-mediated insect cells (Sf21) was used to study the catalytic activities of 24 CYP2D6 variants toward atomoxetine metabolism. The metabolite of atomoxetine (4-hydroxyatomoxetine) was detected by ultra-high performance liquid chromatography-mass spectrometry method. Results: The intrinsic clearance (Vmax/Km) values of most variants were significantly altered when compared with CYP2D6.1. CYP2D6.94, CYP2D6.D336N, CYP2D6.R440C exhibited marked increased values 172, 126, 121% respectively. CYP2D6.89 and CYP2D6.98 exhibited similar catalytic activity as the wild type, whereas 17 variants exhibited significantly decreased values (from 5 to 87%) due to increase Km and/or decrease Vmax values. However, CYP2D6.92 and CYP2D6.96 showed no or few activity because of producing nothing. Conclusions: Our results suggest that most of these newly found variants exhibit significantly changed catalytic activities compared with the wild type. And these findings provide valuable information for the growth and development of personalized medicine in China.

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Effect of CYP2D6 variants on venlafaxine metabolism in vitro

Cited by 15 publications

References 26 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

Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

Effect of 24 Cytochrome P450 2D6 Variants Found in the Chinese Population on Atomoxetine Metabolism in vitro

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