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

Overview

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.

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).