Impact of OCT1 and CYP2D6 Genotypes on Pharmacokinetics of Berberine in Healthy Volunteers

NCT05463003 | Completed

• 1 other identifier: IPHA-2022-002
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Pharmacokinetic Study in Healthy Volunteers

Keywords

Berberine; OCT1; CYP2D6; pharmacogenetic; pharmacokinetic

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Highest concentration (Cmax) of berberine and the berberine metabolites M1-M9.

  48 hours

• Time point of highest concentration (Tmax) of berberine and the berberine metabolites M1-M9.

  48 hours

• Clearance of berberine and the berberine metabolites M1-M9.

  48 hours

• Apparent volume of distribution of berberine and the berberine metabolites M1-M9.

  48 hours

• Changes of plasma concentrations of known endogenous biomarkers like isobutyrylcarnitine

  48 hours

Study Arms (3)

OCT1 and CYP2D6 wildtype genotypes

ACTIVE COMPARATOR

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

OCT1 deficient and CYP2D6 wildtype genotypes

ACTIVE COMPARATOR

In this group, the participants are OCT1 deficient and CYP2D6 wildtype genotype.

Dietary Supplement: Berberine

OCT1 wildtype and CYP2D6 deficient genotypes

ACTIVE COMPARATOR

In this group, the participants are OCT1 wildtype and CYP2D6 deficient genotype.

Dietary Supplement: Berberine

Interventions

Berberine DIETARY_SUPPLEMENT

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

OCT1 and CYP2D6 wildtype genotypes; OCT1 deficient and CYP2D6 wildtype genotypes; OCT1 wildtype and CYP2D6 deficient genotypes

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Medicine Greifswald: lead

Study Sites (1)

University Medicine Greifswald, Institute of Pharmacology

Greifswald, Mecklenburg-Vorpommern, 17489, Germany

Location

Related Publications (1)

• Blocher JA, Meyer-Tonnies MJ, Morof F, Ronnpagel V, Bethmann J, Vollmer M, Engeli S, Tzvetkov MV. Sex-Dependent Effects of CYP2D6 on the Pharmacokinetics of Berberine in Humans. Clin Pharmacol Ther. 2025 Jan;117(1):250-260. doi: 10.1002/cpt.3454. Epub 2024 Nov 3.

  PMID: 39488825 DERIVED

MeSH Terms

Interventions

Berberine

Intervention Hierarchy (Ancestors)

Berberine Alkaloids; Benzylisoquinolines; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring

Study Officials

• Stefan Engeli, Prof.

  Universitätsmedizin Greifswald, Institut für Pharmakologie

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: This Study will be an open label study. Participants will be selected from an existing database of our Institute and are specifically invited according to genotype.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med Stefan Engeli

Model Details: This study should investigate the differences of berberine pharmacokinetic parameters in three cohorts of healthy volunteers: 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

Study Record Dates

• First Submitted: July 8, 2022
• First Posted: July 18, 2022
• Study Start: July 19, 2022
• Primary Completion: November 20, 2022
• Study Completion: December 31, 2022
• Last Updated: December 24, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)