Kinetics of Yohimbine in Humans to Explore Sex and CYP2D6 Genotype Interactions

NCT06939608 | Completed

• 1 other identifier: IPHA-2025-011
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

This study investigates the pharmacokinetics of yohimbine in women and men aged 18 to 40 years to explore sex-specific differences in CYP2D6-dependent drug metabolism. Participants will be classified by their CYP2D6 genotype into extensive metabolizers (EM) and poor metabolizers (PM), forming four distinct study arms: Arm 1) Women, Poor Metabolizers (PM) n=13 Arm 2) Women, Extensive Metabolizers (EM) n=5 Arm 3) Men, Poor Metabolizers (PM) n=13 Arm 4) Men, Extensive Metabolizers (EM) n=5 Each study arm will receive a single oral dose of 50 µg yohimbine (2 x 1 tablets, 25 µg per tablet) and 25 mg of ¹³C₃-caffeine co-administered as a drinking solution. The purpose of this study is:

1. 1.To characterize the pharmacokinetics of yohimbine following a single oral dose in women and men across different CYP2D6 phenotypes.
2. 2.To evaluate yohimbine's suitability as a reliable probe for assessing CYP2D6 activity.
3. 3.To investigate potential interactions between CYP2D6 and CYP1A2, as well as interindividual variability in CYP1A2-dependent caffeine metabolism.

Conditions

Pharmacokinetic Study in Healthy Volunteers

Keywords

sex-specific differences; pharmacokinetics; yohimbine; CYP2D6; genetic polymorphisms; drug metabolism; CYP1A2; ¹³C₃-caffeine

Outcome Measures

Primary Outcomes (3)

• Yohimbine plasma concentration expressed as area under the curve (AUC₀-₂₄h) - arm 1 vs. arm 3

  Difference in plasma concentrations of yohimbine expressed as area under the curve (AUC₀-₂₄h) between women classified as CYP2D6 poor metabolizers (PM) (arm 1) and men classified as CYP2D6 poor metabolizers (PM) (arm 3).

  24 hours

• Yohimbine plasma concentration expressed as area under the curve (AUC₀-₂₄h) - arm 1 vs. arm 2

  Difference in plasma concentrations of yohimbine expressed as area under the curve (AUC₀-₂₄h) between women classified as CYP2D6 poor metabolizers (PM) (arm 1) and women classified as CYP2D6 extensive metabolizers (EM) (arm 2).

  24 hours

• Yohimbine plasma concentration expressed as area under the curve (AUC₀-₂₄h) - arm 3 vs. arm 4

  Difference in plasma concentrations of yohimbine expressed as area under the curve (AUC₀-₂₄h) between men classified as CYP2D6 poor metabolizers (PM) (arm 3) and men classified as CYP2D6 extensive metabolizers (EM) (arm 4).

  24 hours

Secondary Outcomes (5)

• Cmax of yohimbine and 11-OH-yohimbine

  24 hours

• tmax of yohimbine and 11-OH-yohimbine

  24 hours

• Clearance of yohimbine and 11-OH-yohimbine

  24 hours

• Apparent volume of distribution of yohimbine and 11-OH-yohimbine

  24 hours

• 11-OH-Yohimbine plasma concentration expressed as area under the curve (AUC₀-₂₄h)

  24 hours

Other Outcomes (5)

• Cmax of ¹³C₃-caffeine and paraxanthine

  24 hours

• tmax of ¹³C₃-caffeine and paraxanthine

  24 hours

• ¹³C₃-caffeine and paraxanthine plasma concentrations expressed as area under the curve (AUC₀-₂₄h)

  24 hours

Study Arms (4)

Women, Poor Metabolizers (PM)

ACTIVE COMPARATOR

Participants in this arm are women, as identified by their sex assigned at birth, classified as poor metabolizers (PM) based on their CYP2D6 genotype. Poor metabolizers are homozygous for CYP2D6 \*3, \*4, \*5, \*6 or carry heterozygous combinations of these alleles. Participants were selected to achieve best matching between arms according to age, BMI, alcohol consumption and smoking.

Dietary Supplement: Yohimbine; Other: ¹³C₃-caffeine

Women, Extensive Metabolizers (EM)

ACTIVE COMPARATOR

Participants in this arm are women, as identified by their sex assigned at birth, classified as extensive metabolizers (EM) based on their CYP2D6 genotype. Extensive metabolizers are homozygous for CYP2D6 \*1, \*2, \*35 or carry heterozygous combinations of these alleles. Participants were selected to achieve best matching between arms according to age, BMI, alcohol consumption and smoking.

Dietary Supplement: Yohimbine; Other: ¹³C₃-caffeine

Men, Poor Metabolizers (PM)

ACTIVE COMPARATOR

Participants in this arm are men, as identified by their sex assigned at birth, classified as poor metabolizers (PM) based on their CYP2D6 genotype. Poor metabolizers are homozygous for CYP2D6 \*3, \*4, \*5, \*6 or carry heterozygous combinations of these alleles. Participants were selected to achieve best matching between arms according to age, BMI, alcohol consumption and smoking.

Dietary Supplement: Yohimbine; Other: ¹³C₃-caffeine

Men, Extensive Metabolizers (EM)

ACTIVE COMPARATOR

Participants in this arm are men, as identified by their sex assigned at birth, classified as extensive metabolizers (EM) based on their CYP2D6 genotype. Extensive metabolizers are homozygous for CYP2D6 \*1, \*2, \*35 or carry heterozygous combinations of these alleles. Participants were selected to achieve best matching between arms according to age, BMI, alcohol consumption and smoking.

Dietary Supplement: Yohimbine; Other: ¹³C₃-caffeine

Interventions

Yohimbine DIETARY_SUPPLEMENT

A single oral dose of 50 µg yohimbine, administered as 2 x 1 tablets of Yohimbinum hydrochloricum D4® will be co-administered with 25 mg of ¹³C₃-caffeine as drinking solution with 240mL of still water under overnight fasting conditions. A total of 19 blood samples will be collected at defined time points (baseline; 10; 20; 30; 40; 50; 60; 70; 80; 90; 100; 110 min; 2; 3; 4; 6; 8; 10; 24 h). At each time point, 4.9 mL of blood will be drawn for plasma separation to determine yohimbine, the primary metabolite 11-OH-yohimbine and ¹³C₃-caffeine with associated CYP1A2 dependent metabolites.

Men, Extensive Metabolizers (EM); Men, Poor Metabolizers (PM); Women, Extensive Metabolizers (EM); Women, Poor Metabolizers (PM)

¹³C₃-caffeine OTHER

A single oral dose of 25 mg of ¹³C₃-caffeine as a drinking solution will be co-administered with yohimbine with 240 mL of still water under overnight fasting conditions. ¹³C₃-caffeine is a stable isotope-labeled standard probe for phenotyping CYP1A2 activity and assessing potential interactions between CYP2D6 and CYP1A2. Plasma concentrations of ¹³C₃-caffeine with associated CYP1A2 dependent metabolites will be measured at predefined time points, following the sampling schedule outlined for yohimbine.

Men, Extensive Metabolizers (EM); Men, Poor Metabolizers (PM); Women, Extensive Metabolizers (EM); Women, Poor Metabolizers (PM)

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• individuals of both biological sexes, assigned as women or men at birth
• age: ≥ 18 and ≤ 40 years
• possesses the ability to understand the study purpose and design
• contractually capable and provides signed informed consent form
• in good general health or with mild and/or well-managed conditions such as allergies, asthma, hypertension or orthopedic diseases
• taking no more than three chronic medications
• individuals classified as either extensive metabolizers (EM) or poor metabolizers (PM) based on their CYP2D6 genotype:
• Extensive Metabolizers (EM):
• homozygous for CYP2D6 \*1,CYP2D6 \*2, CYP2D6 \*35, or heterozygous combination of any of these alleles
• Poor Metabolizers (PM):
• homozygous for CYP2D6 \*3, CYP2D6 \*4, CYP2D6 \*5, CYP2D6 \*6, or heterozygous combination of any of these alleles

You may not qualify if:

• BMI \> 30 kg/m2 and \< 18 kg/m2
• body weight \< 48 kg
• women: known pregnancy or lactation period; positive urine pregnancy test at screening or kinetic visit
• men: hemoglobin \< 13 g/dl (8,07 mmol/l) women: hemoglobin \< 12 g/dl (7,45 mmol/l)
• elevated liver function tests (1 or more of ALAT, ASAT, yGT, Bilirubin \> 2x ULN)
• reduced renal function (eGFRMDRD \< 60 mL/min/1,7 m2)
• QTcF \> 450 ms in screening ECG
• current or recent psychiatric disorders requiring treatment including depression, bipolar disorder, schizophrenia, psychosis or severe anxiety disorders
• drug dependency at the time of visit
• use of recreational drugs more than twice a week
• any known hypersensitivity or allergic reactions to yohimbine or caffeine
• history of severe hypersensitivity reactions and/or anaphylaxis
• poor venous conditions that make it impossible to place a peripheral venous catheter and regularly draw blood through it
• o) intake of drugs interfering with CYP2D6 and/or CYP1A2 during the past seven days p) intake of yohimbine within 48 hours and caffeine within 16 hours prior to study participation q) engagement in extreme physical activity within 48 hours prior to study participation

Sponsors & Collaborators

• University Medicine Greifswald: lead

Study Sites (1)

University Medicine Greifswald, Institute of Pharmacology

Greifswald, Mecklenburg-Vorpommern, 17489, Germany

Location

MeSH Terms

Interventions

Yohimbine; CID-1 proterin, C elegans

Intervention Hierarchy (Ancestors)

Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: This is an open-label study; no parties involved are masked.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med Stefan Engeli

Model Details: The study is designed as an open-label, four-arm, parallel assignment, single oral dose protocol, stratifying participants by CYP2D6 genotype (extensive vs. poor metabolizers) and biological sex (women vs. men).

Study Record Dates

• First Submitted: March 31, 2025
• First Posted: April 23, 2025
• Study Start: April 28, 2025
• Primary Completion: October 10, 2025
• Study Completion: October 10, 2025
• Last Updated: January 21, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)