Evaluation of Solanidine as an Exogenous Biomarker to Phenotype CYP2D6 Activity in Humans

The study follows an open-label, controlled, parallel-cohort design with four study arms based on CYP2D6 genotype. The study consists of two parts: a Yohimbine and a Potato Part.

Yohimbine Part:

Participants will receive a single oral microdose of 50 μg of yohimbine, administered in a fasted state as 2 x 1 tablets of Yohimbinum hydrochloricum D4® (Deutsche Homöopathie Union, Karlsruhe, Germany, containing 25 μg per tablet). A total of 6 blood samples will be collected at defined time points (baseline; 10; 20; 30; 60; 120 min). At each time point, 5 mL of blood will be drawn for plasma separation to determine yohimbine and the primary metabolite 11-OH-yohimbine. The blood sampling protocol is based on the findings of the YOKI-1 study (protocol number: IPHA-2025-011, Greifswald Ethics Committee Registration number BB 069/25). At baseline, an additional blood sample will be collected for a random determination of solanidine and its metabolites. During the 2.5-hour stay in the CRU, participants will be asked to stay in bed.

Potato Part:

Between the Potato and the Yohimbine Part, a period of 4 weeks in any order is acceptable. The Potato Part is divided into two sequential phases: Phase 1 and Phase 2, both featuring supervised meal ingestion at the clincal research unit. During the three days before each Potato Phase and up to 60 hours afterward, no potato products should be eaten. Otherwise, ad libitum food intake is permitted beginning six hours after the potato-rich meal. Blood samples will be analyzed for solanidine, its CYP2D6-dependent metabolites, and its parent molecules α-solanine and α-chaconine in both Potato Phases. Both Potato Phases must be separated by at least one week.

Phase 1 (0-12 hours postprandial):

An initial baseline blood sample will be collected prior to the ingestion of the potato-rich meal. Participants will receive the potato-rich meal at 8 a.m., and a total of 7 blood samples will be collected at defined time points (baseline, 2, 4, 6, 8, 10, and 12 h).Upon successful completion of the 12-hour blood draw, participants will be discharged from the CRU.

Phase 2 (12-60 hours postprandial):

On a separate scheduled study day, participants will report to the CRU at 7:30 p.m. A baseline blood sample will be collected prior to meal ingestion. Participants will then ingest an identical, defined potato-rich meal at 8:00 p.m. Following meal consumption, participants are permitted to go home for the night. The next morning, starting at 7:30 a.m., blood sampling collections will begin at the designated time points. A total of ten blood samples will be collected at defined time points (baseline, 12, 14, 16, 18, 20, 22, 24 h, 36 h in the next morning and at 60 h in the morning thereafter).

Inclusion criteria

• 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
• ability to maintain and record a detailed dietary protocol focusing on the consumption of potato-based products for the specified duration of the study
• individuals classified as either ultrarapid metabolizers (UM), extensive metabolizers (EM), low intermediate metabolizers (LIM) or poor metabolizers (PM) based on their CYP2D6 genotype:

Poor Metabolizer (PM, Gen-Score 0):

homozygous or compound heterozygous for CYP2D6 *3, CYP2D6 *4, CYP2D6*5, CYP2D6 *6

Low Intermediate Metabolizer (LIM, Gen-Score 0,25 or 0,5):

Homozygous or compound heterozygous for CYP2D6 *9, *10, *41 or compound heterozygous with one allele of CYP2D6 *3, CYP2D6 *4, CYP2D6*5, or CYP2D6*6 and one allele of CYP2D6 *17 (0,5) or CYP2D6 *9, *10, or *41 (0,25)

Extensive Metabolizer (EM, Gene-Score 2):

homozygous or compound heterozygous for CYP2D6 *1, CYP2D6 *2, CYP2D6*35

Ultrarapid Metabolizer (UM, Gen-Score ≥ 3):

homozygous or compound heterozygous for CYP2D6 *1, CYP2D6 *2, CYP2D6*35 with at least one allele duplicated or multiplied

Exclusion criteria

• 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
• intake of drugs interfering with CYP2D6 during the past seven days
• any known hypersensitivity or allergic reactions to yohimbine
• intake of yohimbine within 48 hours prior to study participation
• history of hypersensitivity or allergy to potatoes or nightshade vegetables
• intake of potato-containing meals during the three days before and after eating the potato-rich test meal
• 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
• engagement in extreme physical activity within 48 hours prior to study participation