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

NCT ID: NCT05463003

Last Updated: 2024-12-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-07-19
• Study Completion Date: 2022-12-31

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.

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.

Conditions

Pharmacokinetic Study in Healthy Volunteers

Keywords

Berberine; OCT1; CYP2D6; pharmacogenetic; pharmacokinetic

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Berberine

Intervention Type: 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 deficient and CYP2D6 wildtype genotypes

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

Group Type: ACTIVE_COMPARATOR

Berberine

Intervention Type: 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 wildtype and CYP2D6 deficient genotypes

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

Group Type: ACTIVE_COMPARATOR

Berberine

Intervention Type: 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

Interventions

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

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University Medicine Greifswald

OTHER

Sponsor Role: lead

Responsible Party

Stefan Engeli, MD

Prof. Dr. med Stefan Engeli

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Stefan Engeli, Prof.

Role: PRINCIPAL_INVESTIGATOR

Universitätsmedizin Greifswald, Institut für Pharmakologie

Locations

University Medicine Greifswald, Institute of Pharmacology

Greifswald, Mecklenburg-Vorpommern, Germany

Countries

Germany

References

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.

Reference Type: DERIVED

PMID: 39488825 (View on PubMed)

Other Identifiers

IPHA-2022-002

Identifier Type: -

Identifier Source: org_study_id