Impact of CYP2D6 activity and cachexia progression on enantiomeric alteration of plasma tramadol and its demethylated metabolites and their relationships with central nervous system symptoms in head and neck cancer patients
Impact of CYP2D6 activity and cachexia progression on enantiomeric alteration of plasma tramadol and its demethylated metabolites and their relationships with central nervous system symptoms in head and neck cancer patients
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DOI：
10.1111/bcpt.13528
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发表时间：
2020-10
影响因子：
3.1
通讯作者：
Koji Suzuki;T. Naito;Hironari Tanaka;Kaito Shibata;Y. Yamada;K. Itoh;J. Kawakami
中科院分区：
文献类型：
--
作者：
Koji Suzuki;T. Naito;Hironari Tanaka;Kaito Shibata;Y. Yamada;K. Itoh;J. Kawakami
本研究旨在评估CYP 2D 6活性和恶病质进展对头颈部癌症患者血浆曲马多及其去甲基代谢产物对映体变化的影响。入组了53例接受口服曲马多的头颈癌患者。测定曲马多、O-去甲基曲马多（ODT）和N-去甲基曲马多（NDT）对映体的血浆浓度。根据基因型和格拉斯哥预后评分（GPS）分别评估CYP 2D 6活性评分（AS）和恶病质进展程度。NDT的对映体比例在所有患者中均为（+）-型占优势。CYP 2D 6 AS与血浆（+）-NDT和（-）-NDT浓度呈负相关。GPS 1或2的患者的（+）-曲马多和（+）-ODT血浆浓度高于GPS 0的患者。在GPS 1或2的患者中观察到NDT对映体的代谢率较低。在GPS 1或2的患者中，血浆（-）-曲马多与中枢神经系统症状的发生率相关。总之，CYP 2D 6 AS部分解释了CYP 2D 6活性对血浆曲马多及其去甲基代谢物对映体的贡献。此外，恶病质进展通过减少（+）-曲马多的N-去甲基化升高血浆（+）-曲马多和（+）-ODT水平。
This study aimed to evaluate the influence of CYP2D6 activity and cachexia progression on the enantiomeric alteration of plasma tramadol and its demethylated metabolites in head and neck cancer patients. Fifty‐three head and neck cancer patients receiving oral tramadol were enrolled. The plasma concentrations of tramadol, O‐desmethyltramadol (ODT) and N‐desmethyltramadol (NDT) enantiomers were determined. The CYP2D6 activity score (AS) and degree of cachexia progression were assessed according to genotype and the Glasgow Prognostic Score (GPS), respectively. The enantiomeric ratio of NDT was (+)‐form dominant in all patients. CYP2D6 AS had negative correlations with the plasma concentrations of (+)‐NDT and (−)‐NDT. The plasma concentrations of (+)‐tramadol and (+)‐ODT were higher in patients with GPS 1 or 2 than in those with GPS 0. Lower metabolic ratios to NDT enantiomers were observed in patients with GPS 1 or 2. In patients with GPS 1 or 2, the plasma (−)‐tramadol was associated with the incidence of central nervous system symptoms. In conclusion, CYP2D6 AS partially explained the contribution of CYP2D6 activity to plasma tramadol and its demethylated metabolite enantiomers. Additionally, cachexia progression elevated the plasma (+)‐tramadol and (+)‐ODT levels through the reduction of N‐demethylation of (+)‐tramadol.