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.

Clinical trial registration: EudraCT2017-001801-34.

Fig. 1

Clinical trial design. MDZ midazolam, PAR paroxetine, YOH yohimbine

Fig. 2

Yohimbine plasma concentration–time curves divided into genotypes after administration of yohimbine 5 mg in linear and logarithmic presentations. Red points and line: poor metaboliser; blue points and line: intermediate metaboliser, green points and line: extensive metaboliser

Fig. 3

11-OH-yohimbine plasma concentration–time curves divided into genotypes after administration of yohimbine 5 mg in linear and logarithmic presentations. Red diamond and line: poor metaboliser; blue diamonds and line: intermediate metaboliser; green diamonds and line: extensive metaboliser

Fig. 4

Yohimbine plasma concentration–time curves divided into genotypes after administration of yohimbine 50 µg in linear and logarithmic presentations. Red points and line: poor metaboliser; blue points and line: intermediate metaboliser; green points and line: extensive metaboliser

Fig. 5

11-OH-yohimbine plasma concentration–time curves divided into genotypes after administration of yohimbine 50 µg in linear and logarithmic presentations. Red diamonds and line: poor metaboliser; blue diamonds and line: intermediate metaboliser; green diamonds and line: extensive metaboliser

Fig. 6

Comparison of yohimbine clearance after oral administration of yohimbine 5 mg and yohimbine 50 µg alone and during paroxetine

Fig. 7

Relationship between yohimbine clearance and cytochrome P450 2D6 (CYP2D6) activity score after single oral administration of yohimbine 50 µg