CYP2D6 phenotype explains reported yohimbine concentrations in four severe acute intoxications.
CYP2D6 phenotype explains reported yohimbine concentrations in four severe acute intoxications.
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DOI：
10.1007/s00204-021-03082-4
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发表时间：
2021-08
影响因子：
6.1
通讯作者：
Mikus G
中科院分区：
文献类型：
--
作者：
Mueller-Schoell A;Michelet R;Weinelt F;Kloft C;Mikus G
吲哚生物碱育亨宾是一种 α-2 受体拮抗剂，具有拟交感神经作用。已经报道了几起育亨宾中毒病例，最近的一起涉及四人服用含有育亨宾的药物粉末。所有人员均出现严重中毒症状并被送往医院。尽管假设所有个体都服用了相同剂量的药物粉末，但毒理学分析显示育亨宾血液浓度为 249–5631 ng/mL，相当于 22 倍的差异。这种高变异性的原因仍有待阐明。我们利用最近报道的育亨宾代谢知识以及最先进的非线性混合效应建模和模拟，结果表明患者的细胞色素 P450 2D6 (CYP2D6) 表型可以解释摄入相同剂量育亨宾后测量浓度的巨大差异。我们的研究结果既可用于确定育亨宾治疗用途的安全剂量，也可用于解释用药过量的个别病例。
The indole alkaloid yohimbine is an alpha-2 receptor antagonist used for its sympathomimetic effects. Several cases of yohimbine intoxication have been reported and the most recent one involved four individuals taking a yohimbine-containing drug powder. All individuals developed severe intoxication symptoms and were admitted to the hospital. Even though all individuals were assumed to have taken the same dose of the drug powder, toxicology analyses revealed yohimbine blood concentrations of 249–5631 ng/mL, amounting to a 22-fold difference. The reason for this high variability remained to be elucidated. We used recently reported knowledge on the metabolism of yohimbine together with state-of-the art nonlinear mixed-effects modelling and simulation and show that a patient’s cytochrome P450 2D6 (CYP2D6) phenotype can explain the large differences observed in the measured concentration after intake of the same yohimbine dose. Our findings can be used both for the identification of safe doses in therapeutic use of yohimbine and for an explanation of individual cases of overdosing.
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