Oral Yohimbine as a New Probe Drug to Predict CYP2D6 Activity: Results of a Fixed-Sequence Phase I Trial
Oral Yohimbine as a New Probe Drug to Predict CYP2D6 Activity: Results of a Fixed-Sequence Phase I Trial
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DOI：
10.1007/s40262-020-00862-6
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发表时间：
2020-02-15
影响因子：
4.5
通讯作者：
Mikus, Gerd
中科院分区：
文献类型：
--
作者：
Vay, Manuela;Meyer, Marleen Julia;Mikus, Gerd
目的 测定口服单剂量育亨宾 5 mg 和微剂量育亨宾 50 μg 后与不同细胞色素 P450 (CYP) 2D6 基因型相关的育亨宾药代动力学。使用CYP2D6抑制剂帕罗西汀研究其对育亨宾药代动力学的影响。应用微剂量的咪达唑仑来评估育亨宾对 CYP3A 活性的可能影响以及将微剂量的育亨宾和咪达唑仑组合同时测定 CYP2D6 和 CYP3A 活性的可能性。方法 在一项固定序列临床试验中，16 名已知 CYP2D6 基因型的健康志愿者[强代谢型 (10)、中代谢型 (2) 和弱代谢型 (4)] 接受口服育亨宾 50 μg、基线时和帕罗西汀治疗期间育亨宾 5 mg 作为 CYP2D6 抑制剂。每次同时施用咪达唑仑(30μg)以测定CYP3A活性。使用经过验证的液相色谱-串联质谱测定法对育亨宾、其主要代谢物 11-OH-育亨宾、咪达唑仑和帕罗西汀的血浆浓度进行定量。结果 育亨宾的药代动力学变化很大，并且观察到 CYP2D6 基因型依赖性清除率。育亨宾 5 mg 后，清除率范围为 25.3 至 15,864 mL/min，育亨宾 50 μg 后，清除率范围为 39.6 至 38,822 mL/min。帕罗西汀在 CYP2D6 强代谢者中导致清除率降低五倍以上，而在弱代谢者中清除率不受影响。根据微剂量咪达唑仑的测量，育亨宾不会改变 CYP3A 活性。结论 育亨宾的药代动力学与 CYP2D6 高度相关，CYP2D6 抑制剂帕罗西汀引起的清除抑制进一步支持了这一点。根据这些数据，育亨宾被认为是预测 CYP2D6 活性的合适探针药物。此外，微剂量可以与微剂量咪达唑仑联合使用，同时评估CYP2D6和CYP3A活性，而探针药物之间没有任何相互作用，并且因为微剂量不发挥药理作用。
Objective Yohimbine pharmacokinetics were determined after oral administration of a single oral dose of yohimbine 5 mg and a microdose of yohimbine 50 mu g in relation to different cytochrome P450 (CYP) 2D6 genotypes. The CYP2D6 inhibitor paroxetine was used to investigate the influence on yohimbine pharmacokinetics. Microdosed midazolam was applied to evaluate a possible impact of yohimbine on CYP3A activity and the possibility of combining microdosed yohimbine and midazolam to simultaneously determine CYP2D6 and CYP3A activity. Methods In a fixed-sequence clinical trial, 16 healthy volunteers with a known CYP2D6 genotype [extensive (10), intermediate (2) and poor (4) metaboliser] received an oral dose of yohimbine 50 mu g, yohimbine 5 mg at baseline and during paroxetine as a CYP2D6 inhibitor. Midazolam (30 mu g) was co-administered to determine CYP3A activity at each occasion. Plasma concentrations of yohimbine, its main metabolite 11-OH-yohimbine, midazolam and paroxetine were quantified using validated liquid chromatography-tandem mass spectrometry assays. Results Pharmacokinetics of yohimbine were highly variable and a CYP2D6 genotype dependent clearance was observed. After yohimbine 5 mg, the clearance ranged from 25.3 to 15,864 mL/min and after yohimbine 50 mu g, the clearance ranged from 39.6 to 38,822 mL/min. A more than fivefold reduction in clearance was caused by paroxetine in CYP2D6 extensive metabolisers, while the clearance in poor metabolisers was not affected. Yohimbine did not alter CYP3A activity as measured by microdosed midazolam. Conclusions The pharmacokinetics of yohimbine were highly correlated with CYP2D6, which was further supported by the clearance inhibition caused by the CYP2D6 inhibitor paroxetine. With these data, yohimbine is proposed to be a suitable probe drug to predict CYP2D6 activity. In addition, the microdose can be used in combination with microdosed midazolam to simultaneously evaluate CYP2D6 and CYP3A activity without any interaction between the probe drugs and because the microdoses exert no pharmacological effects.