Impact of OCT1 and CYP2D6 Genotypes on Pharmacokinetics of Berberine in Healthy Volunteers (BERKI-1)

This study should investigate the differences of berberine pharmacokinetic parameters in three cohorts of healthy volunteers with distinct genotypes of the organic cation transporter 1 (OCT1) gene and the cytochrome P450 2D6 (CYP2D6) gene:

Cohort 1a) OCT1 and CYP2D6 wildtype genotypes n = 10 Cohort 1b) OCT1 and CYP2D6 wildtype genotypes n = 10 Cohort 2) OCT1 deficient/CYP2D6 wildtype genotypes n = 10 Cohort 3) OCT1 wildtype/CYP2D6 deficient genotypes n = 10 Participants will be selected from the study volunteers database of the Institute of Pharmacology in Greifswald according to their OCT1 and CYP2D6 genotypes and to achieve best matching according to sex, age, BMI, alcohol consumption and smoking between Cohort 1a and 2 or Cohort 1b and 3, respectively.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetic Study in Healthy Volunteers
• Intervention / Treatment: Dietary supplement: Berberine

Detailed Description

A single dose of 1000 mg berberine will be administered in two capsules with 250 ml of still water in the overnight fasting condition. A total of 12 blood samples will be taken at defined time points (baseline, 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 24; 48 h). At each time point, blood will be collected in 2x 7.5 ml tubes for collecting serum and plasma samples to determine berberine, its metabolites and biomarkers of OCT1 transport and CYP2D6 enzymatic activity. At baseline, additional 2x 2.7 ml blood tubes will be collected for DNA isolation.

The total amount of blood collected for each participant is 190 ml at the three Pharmacokinetic Visits and 10 ml at the Screening Visit. Every hour, participants will drink 100 ml of sparkling water to stimulate intestinal peristalsis and promote transport of the capsule. After 2 hours, the participants may drink a cup of tea or coffee and after 4 hours they will be served a meal. Urine will be collected during the first 10 h after administration. Monitoring of vital parameters, e.g. blood pressure and heart rate, will take place for the first 4 hours after administration. The participants will stay in the Clinical Research Unit of the Institute of Pharmacology for the first 10 hours after administration.

• Study Type: Interventional
• Enrollment (Actual): 42
• 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: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• any sex
• OCT1 wildtype: homozygous for OCT*1
• OCT "poor transporter": homozygous or heterozygous for OCT1*3, *4, *5, *6
• CYP2D6 wildtype: homozygous or heterozygous for *1, *2, *35
• CYP2D6 "poor metabolizer": homozygous or heterozygous for *3, *4, *5, *6
• age between 18 and 50 years
• understands the study purpose and design
• contractually capable and provides signed informed consent form
• healthy condition or mild and/or well treated forms of allergies, asthma, hypertension, and orthopedic diseases
• a maximum of 3 chronically taken drugs not interfering with OCT1 and CYP2D6 activities

Exclusion Criteria:

• BMI > 35 kg/m2 and <18 kg/m2
• known pregnancy or lactation period
• women: positive urine pregnancy test at screening or pharmacokinetic visit
• anemia (hemoglobin < 13 g/dl (8,07 mmol/l) in men or < 12 g/dl (7,45 mmol/l) in women
• elevated liver function tests (> 2x ULN)
• reduced renal function (eGFRMDRD < 60 ml/min/1,7m2)
• psychiatric disease or drug dependency at time of visit
• use of recreational drugs more than twice a week
• poor venous conditions that make it impossible to place a peripheral venous catheter and regularly draw blood through it

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: OCT1 and CYP2D6 wildtype genotypes; In this group, the participants are OCT1 and CYP2D6 wildtype genotypes. The participants are selected to achieve best matching according to sex, age, BMI, alcohol consumption and smoking between arm (cohort) 1 and arm (cohort) 2 and 3, respectively.	Dietary supplement: Berberine; A single dose of 1000 mg berberine in two capsules will be administered with 250 ml of still water in the overnight fasting condition. A total of 12 blood samples will be taken at defined time points (baseline, 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 24; 48 h). At each time point, blood will be collected in 2x 7.5 ml tubes for collecting serum and plasma samples to determine berberine, its metabolites and biomarkers of OCT1 transport and CYP2D6 enzymatic activity
Active Comparator: OCT1 deficient and CYP2D6 wildtype genotypes; In this group, the participants are OCT1 deficient and CYP2D6 wildtype genotype.	Dietary supplement: Berberine; A single dose of 1000 mg berberine in two capsules will be administered with 250 ml of still water in the overnight fasting condition. A total of 12 blood samples will be taken at defined time points (baseline, 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 24; 48 h). At each time point, blood will be collected in 2x 7.5 ml tubes for collecting serum and plasma samples to determine berberine, its metabolites and biomarkers of OCT1 transport and CYP2D6 enzymatic activity
Active Comparator: OCT1 wildtype and CYP2D6 deficient genotypes; In this group, the participants are OCT1 wildtype and CYP2D6 deficient genotype.	Dietary supplement: Berberine; A single dose of 1000 mg berberine in two capsules will be administered with 250 ml of still water in the overnight fasting condition. A total of 12 blood samples will be taken at defined time points (baseline, 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 24; 48 h). At each time point, blood will be collected in 2x 7.5 ml tubes for collecting serum and plasma samples to determine berberine, its metabolites and biomarkers of OCT1 transport and CYP2D6 enzymatic activity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Berberine plasma and serum concentration expressed as Area under the Curve (AUC0-48 hours).	Difference in berberine plasma and serum concentrations expressed as Area under the Curve (AUC0-48 hours) between 1) OCT1 wildtype and OCT1 loss of function cohorts (Cohort 1a vs. Cohort 2), and 2) between CYP2D6 wildtype and CYP2D6 loss of function cohorts (Cohort 1b vs. Cohort 3).	48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Highest concentration (Cmax) of berberine and the berberine metabolites M1-M9.	Differences in Cmax of berberine and the berberine metabolites M1-M9 between the above described cohorts.	48 hours
Time point of highest concentration (Tmax) of berberine and the berberine metabolites M1-M9.	Differences in Tmax of berberine and the berberine metabolites M1-M9 between the above described cohorts.	48 hours
Clearance of berberine and the berberine metabolites M1-M9.	Differences in Clearance of berberine and the berberine metabolites M1-M9 between the above described cohorts.	48 hours
Apparent volume of distribution of berberine and the berberine metabolites M1-M9.	Differences in apparent volume of distribution of berberine and the berberine metabolites M1-M9 between the above described cohorts.	48 hours
Changes of plasma concentrations of known endogenous biomarkers like isobutyrylcarnitine	Changes of plasma concentrations of known endogenous biomarkers like isobutyrylcarnitine. These will be monitored during all time points after berberine administration and their changes over time will be related to the concentration changes of berberine and its major metabolites over time.	48 hours

Collaborators and Investigators

• Sponsor: University Medicine Greifswald
• Investigators: Principal Investigator: Stefan Engeli, Prof., Universitätsmedizin Greifswald, Institut für Pharmakologie

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2022
• Primary Completion (Actual): November 20, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: July 8, 2022
• First Submitted That Met QC Criteria: July 13, 2022
• First Posted (Actual): July 18, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 19, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: pharmacokinetic; Berberine; CYP2D6; OCT1; pharmacogenetic
• Other Study ID Numbers: IPHA-2022-002

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