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

Abstract

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.

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

“…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].…”

“…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.…”

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

“…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.…”

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

“…As a consequence, in our study the relative clearance of CYP2D6.2 (23.43% of CYP2D6.1) and CYP2D6.10 (3.11% of CYP2D6.1) were both presented significantly decreased. These results were consistent with previous work and indicate that it is appropriate to use our CYP expression and in vitro metabolism system for analyzing the catalytic activities of the other CYP2D6 variants 21,22,26,27…”