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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 7/2020

Open Access 01-07-2020 | Pharmacokinetics | Original Research Article

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

Authors: Manuela Vay, Marleen Julia Meyer, Antje Blank, Gisela Skopp, Peter Rose, Mladen Vassilev Tzvetkov, Gerd Mikus

Published in: Clinical Pharmacokinetics | Issue 7/2020

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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.

Clinical Trial Registration

EudraCT2017-001801-34.
Appendix
Available only for authorised users
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Metadata
Title
Oral Yohimbine as a New Probe Drug to Predict CYP2D6 Activity: Results of a Fixed-Sequence Phase I Trial
Authors
Manuela Vay
Marleen Julia Meyer
Antje Blank
Gisela Skopp
Peter Rose
Mladen Vassilev Tzvetkov
Gerd Mikus
Publication date
01-07-2020
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 7/2020
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-020-00862-6

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