Kinetics of Yohimbine in Humans to Explore Sex and CYP2D6 Genotype Interactions (YOKI-1)

Kinetics of Yohimbine in Humans to Explore Sex and CYP2D6 Genotype Interactions - YOKI-1 Study

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

Study Overview

• Status: Completed
• Conditions: Pharmacokinetic Study in Healthy Volunteers
• Intervention / Treatment: Dietary supplement: Yohimbine; Other: ¹³C₃-caffeine

Detailed Description

The study is designed as an open-label, single-dose protocol with four study arms based on sex and CYP2D6 genotype. A single oral dose of yohimbine and ¹³C₃-caffeine will be administered with 240 ml 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. One additional blood sample (EDTA tube) for potential future genetic analysis, will be collected together with the baseline kinetic samples.

For each participant, a total of approximately 98 mL of blood will be collected during the kinetic visits and an additional 12 mL during the screening visit.

Following the administration of yohimbine and 13C3-caffeine, participants will consume 200 mL of sparkling water every hour to stimulate gastrointestinal peristalsis facilitate substance transport. Two hours post-administration, participants may have a cup of tea or coffee, while a standardized meal will be served four hours after dosing.

Urine samples will be collected over 24 hours in three intervals (0-4 h, 5-10 h, 11-24 h). Blood pressure and heart rate monitoring will be conducted during the initial four hours and participants will remain in the Clinical Research Unit of the Institute of Pharmacology for the first 10 hours post-administration. At 24 hours post-dosing, participants will return to the Clinical Research Unit for the final scheduled blood collection and to provide their last urine sample (11-24 h).

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Mecklenburg-Vorpommern
    • Greifswald, Mecklenburg-Vorpommern, Germany, 17489
      • University Medicine Greifswald, Institute of Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. individuals of both biological sexes, assigned as women or men at birth
2. age: ≥ 18 and ≤ 40 years
3. possesses the ability to understand the study purpose and design
4. contractually capable and provides signed informed consent form
5. in good general health or with mild and/or well-managed conditions such as allergies, asthma, hypertension or orthopedic diseases
6. taking no more than three chronic medications
7. 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

Exclusion Criteria:

1. BMI > 30 kg/m2 and < 18 kg/m2
2. body weight < 48 kg
3. women: known pregnancy or lactation period; positive urine pregnancy test at screening or kinetic visit
4. men: hemoglobin < 13 g/dl (8,07 mmol/l) women: hemoglobin < 12 g/dl (7,45 mmol/l)
5. elevated liver function tests (1 or more of ALAT, ASAT, yGT, Bilirubin > 2x ULN)
6. reduced renal function (eGFRMDRD < 60 mL/min/1,7 m2)
7. QTcF > 450 ms in screening ECG
8. current or recent psychiatric disorders requiring treatment including depression, bipolar disorder, schizophrenia, psychosis or severe anxiety disorders
9. drug dependency at the time of visit
10. use of recreational drugs more than twice a week
11. any known hypersensitivity or allergic reactions to yohimbine or caffeine
12. history of severe hypersensitivity reactions and/or anaphylaxis
13. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Women, Poor Metabolizers (PM); 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; 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.; Other: ¹³C₃-caffeine; 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.
Active Comparator: Women, Extensive Metabolizers (EM); 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; 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.; Other: ¹³C₃-caffeine; 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.
Active Comparator: Men, Poor Metabolizers (PM); 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; 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.; Other: ¹³C₃-caffeine; 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.
Active Comparator: Men, Extensive Metabolizers (EM); 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; 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.; Other: ¹³C₃-caffeine; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of yohimbine and 11-OH-yohimbine	Differences in maximum concentration (Cmax) of yohimbine and the primary metabolite 11-OH-yohimbine between CYP2D6 poor metabolizers (PM) and extensive metabolizers (EM) within the same sex (Arm 1 vs. Arm 2 and Arm 3 vs. Arm 4) and between women and men classified as PM (Arm 1 vs. Arm 3) and EM (Arm 2 vs. Arm 4).	24 hours
tmax of yohimbine and 11-OH-yohimbine	Differences in time to maximum concentration (tmax) of yohimbine and the primary metabolite 11-OH-yohimbine between CYP2D6 poor metabolizers (PM) and extensive metabolizers (EM) within the same sex (Arm 1 vs. Arm 2 and Arm 3 vs. Arm 4) and between women and men classified as PM (Arm 1 vs. Arm 3) and EM (Arm 2 vs. Arm 4).	24 hours
Clearance of yohimbine and 11-OH-yohimbine	Differences in total and renal clearance of yohimbine and the primary metabolite 11-OH-yohimbine between CYP2D6 poor metabolizers (PM) and extensive metabolizers (EM) within the same sex (Arm 1 vs. Arm 2 and Arm 3 vs. Arm 4) and between women and men classified as PM (Arm 1 vs. Arm 3) and EM (Arm 2 vs. Arm 4).	24 hours
Apparent volume of distribution of yohimbine and 11-OH-yohimbine	Differences in apparent volume of distribution of yohimbine and the primary metabolite 11-OH-yohimbine between CYP2D6 poor metabolizers (PM) and extensive metabolizers (EM) within the same sex (Arm 1 vs. Arm 2 and Arm 3 vs. Arm 4) and between women and men classified as PM (Arm 1 vs. Arm 3) and EM (Arm 2 vs. Arm 4).	24 hours
11-OH-Yohimbine plasma concentration expressed as area under the curve (AUC₀-₂₄h)	Differences in plasma concentrations of 11-OH-yohimbine expressed as area under the curve (AUC₀-₂₄h) between CYP2D6 poor metabolizers (PM) and extensive metabolizers (EM) within the same sex (Arm 1 vs. Arm 2 and Arm 3 vs. Arm 4) and between women and men classified as PM (Arm 1 vs. Arm 3) and EM (Arm 2 vs. Arm 4).	24 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of ¹³C₃-caffeine and paraxanthine	Differences in maximum concentration (Cmax) of ¹³C₃-caffeine and its metabolite paraxanthine will be analyzed across all study arms and correlated with Cmax values of yohimbine and its primary metabolite 11-OH-yohimbine to assess potential interactions between CYP2D6 (involved in yohimbine metabolism) and CYP1A2 (involved in ¹³C₃-caffeine metabolism).	24 hours
tmax of ¹³C₃-caffeine and paraxanthine	Differences in time to maximum concentration (tmax) of ¹³C₃-caffeine and its metabolite paraxanthine will be analyzed across all study arms and correlated with tmax values of yohimbine and its primary metabolite 11-OH-yohimbine to assess potential interactions between CYP2D6 (involved in yohimbine metabolism) and CYP1A2 (involved in ¹³C₃-caffeine metabolism).	24 hours
¹³C₃-caffeine and paraxanthine plasma concentrations expressed as area under the curve (AUC₀-₂₄h)	Differences in plasma concentrations of ¹³C₃-caffeine and its metabolite paraxanthine expressed as area under the curve (AUC₀-₂₄h) will be analyzed across all study arms and correlated with AUC₀-₂₄h values of yohimbine and its primary metabolite 11-OH-yohimbine to assess potential interactions between CYP2D6 (involved in yohimbine metabolism) and CYP1A2 (involved in ¹³C₃-caffeine metabolism)	24 hours
Renal clearance of ¹³C₃-caffeine and paraxanthine	Differences in renal clearance of ¹³C₃-caffeine and its metabolite paraxanthine will be analyzed across all study arms and correlated with renal clearance values of yohimbine and its primary metabolite 11-OH-yohimbine to assess potential interactions between CYP2D6 (involved in yohimbine metabolism) and CYP1A2 (involved in ¹³C₃-caffeine metabolism).	24 hours
Apparent volume of distribution of ¹³C₃-caffeine and paraxanthine	Differences in apparent volume of distribution of ¹³C₃-caffeine and its metabolite paraxanthine will be analyzed across all study arms and correlated with apparent volume of distribution values of yohimbine and its primary metabolite 11-OH-yohimbine to assess potential interactions between CYP2D6 (involved in yohimbine metabolism) and CYP1A2 (involved in ¹³C₃-caffeine metabolism).	24 hours

Collaborators and Investigators

• Sponsor: University Medicine Greifswald

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2025
• Primary Completion (Actual): October 10, 2025
• Study Completion (Actual): October 10, 2025

Study Registration Dates

• First Submitted: March 31, 2025
• First Submitted That Met QC Criteria: April 14, 2025
• First Posted (Actual): April 23, 2025

Study Record Updates

• Last Update Posted (Actual): January 21, 2026
• Last Update Submitted That Met QC Criteria: January 20, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: pharmacokinetics; CYP2D6; drug metabolism; genetic polymorphisms; CYP1A2; sex-specific differences; yohimbine; ¹³C₃-caffeine
• Additional Relevant MeSH Terms: Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Indoles; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Yohimbine; CID-1 proterin, C elegans
• Other Study ID Numbers: IPHA-2025-011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No