Oral Yohimbine as a New Probe Drug to Predict CYP2D6 Activity: Results of a Fixed-Sequence Phase I Trial

Abstract

Objective Yohimbine pharmacokinetics were determined after oral administration of a single oral dose of yohimbine 5 mg and a microdose of yohimbine 50 µg 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 µg, yohimbine 5 mg at baseline and during paroxetine as a CYP2D6 inhibitor. Midazolam (30 µg) 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 µg, 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. Key PointsThis is the first study to demonstrate the major cytochrome P450 2D6 dependency of the clearance of yohimbine.Yohimbine as a potential probe drug for cytochrome P450 2D6 activity can also be used in a microdose setting to minimise the risk for any potential study population.

Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups

“…While the low-dose tamoxifen study in the preventive setting was not sufficiently powered to detect the proposed relationship between endoxifen and treatment response, it is possible that different endoxifen target thresholds will be identified for different treatment settings and that there might be no minimum endoxifen target concentration for efficacy in the preventive setting. The suggested trial could also integrate routine CYP2D6 phenotyping using, e.g., a microdosed probe substance, such as yohimbine, and assess the correlation of CYP2D6 phenotype and C SS,min ENDX [ 55 ]. The CYP2D6 phenotype could then be used to guide initial dose selection followed by therapeutic drug monitoring-guided dose refinement as part of a previously proposed model-informed precision dosing framework [ 11 , 31 ].…”

CYP2D6 phenotype explains reported yohimbine concentrations in four severe acute intoxications

“…Based on the estimated clearance values, all four patients were phenotypic CYP2D6 intermediate metabolisers with decreased metabolic activity. In addition, there might have been some degree of autoinhibition which has been reported for yohimbine before (Vay et al 2020). Yet, since very high doses such as 5 g have never been investigated before, the degree of autoinhibition and its contribution to the observed decreased clearance is unknown and needs further evaluation.…”

“…The authors highlighted the potential risk for yohimbine overdosing and we appreciate their important contribution to defining a therapeutic window for yohimbine. However, while the authors focused on the high interindividual variability in bioavailability as a possible explanation for the very different concentrations measured between 10 and 11 h after intake of yohimbine, we think that newly emerged knowledge on its pharmacokinetics and metabolism (Vay et al 2020) together with pharmacokinetic simulations can further elucidate reasons for the observed high yohimbine concentrations.…”

“…Yohimbine is a plant-derived indole alkaloid and alpha-2 receptor antagonist (Swann et al 2013 ), historically used for erectile dysfunction (Wishart et al 2018 ) but also abused in the bodybuilding community (Drevin et al 2020 ). Recently, it has received increased attention as a promising compound for the microdose-based identification of a patient’s cytochrome P450 (CYP) metaboliser status (Vay et al 2020 ). Over the years, several cases of yohimbine intoxication have been reported (Giampreti et al 2009 ; Anderson et al 2013 ; Gicquel et al 2016 ; Drevin et al 2020 ).…”

“…There are only a few publications on the pharmacokinetics of yohimbine, whose bioavailability is highly variable (Guthrie et al 1990 ) and elimination has been poorly characterised for a long time. Recently published new data identified the highly polymorphic CYP2D6 as a major contributor to the clearance of yohimbine (Vay et al 2020 ). In this work, the pharmacokinetics of a single oral dose of 5 mg yohimbine was characterised in CYP2D6 genotyped Caucasian volunteers.…”