CYP2D6 gene polymorphism and apatinib affect the metabolic profile of fluvoxamine

Abstract

This study aimed 1) to investigate the influence of CYP2D6 variants on the catalyzing of fluvoxamine, and 2) to study the interaction between fluvoxamine and apatinib. An enzymatic reaction system was setup and the kinetic profile of CYP2D6 in metabolizing fluvoxamine was determined. In vivo, drug-drug interaction was investigated using Sprague–Dawley (SD) rats. Fluvoxamine was given gavage with or without apatinib. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the concentrations of fluvoxamine and desmethyl-fluvoxamine. The results demonstrated that the relative clearance rates of CYP2D6.A5V, V104A, D337G, F164L, V342M, R440C and R497C increased significantly compared with CYP2D6.1, ranging from 153.626% ± 6.718% to 394.310% ± 33.268%. The activities of other variants reduced to different extent, or even lost function, but there was no statistical difference. The IC50 of apatinib against fluvoxamine disposition was determined, which is 0.190 μM in RLM and 6.419 μM in HLM, respectively. In vivo, apatinib can enhance the plasma exposure of fluvoxamine remarkably characterized by increased AUC, Tmax and Cmax. Meanwhile, the produce of desmethyl fluvoxamine was dramatically inhibited, both AUC and Cmax decreased significantly. Mechanistically, apatinib inhibit the generation of fluvoxamine metabolite with a mixed manner both in RLM and HLM. Furthermore, there were differences in the potency of apatinib in suppressing fluvoxamine metabolism among CYP2D6.1, 2 and 10. In conclusion, CYP2D6 gene polymorphisms and drug-drug interaction can remarkably affect the plasma exposure of fluvoxamine. The present study provides basis data for guiding individual application of fluvoxamine.

The impacts of natural product miltirone and the CYP2D6 pharmacogenetic phenotype on fluoxetine metabolism

“…As shown in Table 5 , to understand the differences in the metabolism of diverse antidepressants by reported CYP2D6 variants, we compared the relative clearance values of venlafaxine, citalopram, olanzapine, and fluvoxamine reported with those of fluoxetine in this study ( Hu et al, 2016 ; Ye et al, 2022 ; Zhan et al, 2016 ; Zhou et al, 2016 ).…”

“…As shown in Table 5 , the relative clearance values of venlafaxine by all CYP2D6 variants decreased significantly compared with that of the wild-type, which is different from the results for olanzapine and citalopram reported previously or for fluoxetine in this study ( Hu et al, 2016 ; Zhan et al, 2016 ; Zhou et al, 2016 ). Furthermore, more than 8 CYP2D6 variants exhibited slightly increased enzymatic activity (>10%) toward fluoxetine and fluvoxamine among these variants ( Ye et al, 2022 ), but only 2 variants exhibited slightly increased enzymatic activity toward olanzapine (CYP2D6*V342M, CYP2D6*F219S) and citalopram (CYP2D6*89/L142S, CYP2D6*98/H463D). Similar to the results for olanzapine and citalopram, 5 variants (CYP2D6*10, CYP2D6*87/A5V, CYP2D6*90/K147R, CYP2D6*F164L and CYP2D6*R440C) exhibited notably decreased enzymatic activity (>10%) for fluoxetine but increased metabolic activity for fluvoxamine.…”

“…To our knowledge, the effect of CYP2D6 polymorphism on fluoxetine metabolism has not been reported. Therefore, the enzymatic activities of these CYP2D6 variants toward fluoxetine were characterized in insect microsomes expressing wild-type and variant CYP2D6 according to a previously reported method ( Ye et al, 2022 ).…”

Pharmacokinetics and bioequivalence studies of fluvoxamine maleate tablets in healthy Chinese subjects

“…Previous studies have found that the exposure of children is greater than that of adolescents after administration, and the pharmacokinetic parameters of adolescents are similar to those of adults, suggesting that fluvoxamine is mainly metabolized by CYP 2D6 enzymes (Zastrozhin et al, 2021). Results of research provide evidence of the nonlinear, sex‐dependent pharmacokinetics of fluvoxamine (Ye et al, 2022). The patients were prescribed 50 mg of fluvoxamine twice a day for the first 14 days and 100 mg twice a day thereafter.…”

The effect of icotinib or apatinib on the pharmacokinetic profile of oxycodone in rats and the underlying mechanism

“…There is in vitro evidence that icotinib inhibits CYP3A ( Chen et al, 2015 ; Zhuang et al, 2016 ). Furthermore, apatinib can inhibit the activity of many cytochrome P450 enzymes, including CYP2D6 ( Ye et al, 2022 ; Zhou et al, 2014 ). Therefore, the co-administration of icotinib or apatinib with oxycodone could result in a fluctuation of drug response.…”