Effects of Kudzu Root (Gegen) on Drug-Metabolizing Enzymes and Blood Clotting in Healthy Volunteers

Gegen (Radix Puerariae lobatae) is a common traditional Chinese herbal medicine. Preclinical data indicate its potential to inhibit cytochrome P450 enzymes, which may lead to herb-drug interactions. However, robust clinical evidence in humans remains insufficient.This randomized, two-period study enrolled healthy Chinese adults, with participants allocated to parallel low-dose and high-dose Gegen groups. A six-probe drug cocktail was administered before and after Gegen intake to characterize in vivo CYP enzyme activity under intervention and control conditions.Serial blood samples were collected to quantify probe substrates and metabolites for CYP phenotyping, and to measure circulating biomarkers of coagulation and endothelial function for safety assessment. This study evaluated Gegen's effects on six key human CYP isoforms (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A). Enzyme activity was assessed using metabolic ratios and AUC-based drug exposure comparisons. Specific coagulation and endothelial biomarkers, including thromboxane B2 and soluble thrombomodulin, were examined. Adverse events were monitored throughout the study.The results of this study provide insight into the isoform-specific modulation of CYP enzymes by Gegen and its potential implications for herb-drug interactions involving CYP-metabolized medications.

Inclusion criteria

• Male and non-pregnant female Chinese subjects, 20 - 45 years of age.
• Body weight within 15% of ideal weight (according to the Metropolitan InsuranceCompany Bulletin).
• Accessible vein for blood sampling.
• High probability for compliance and completion of the study.
• Female subjects who are surgically sterile or post-menopausal. Or female subjects of child bearing potential agree to practice abstinence or take effective contraceptive methods (e.g. non-hormonal intra-uterine device, consistent condom plus spermicide use or consistent cervical cap with spermicide) from the start of screening until two weeks of last dose administration to prevent pregnancy.
• Male subjects agree to practice abstinence or take effective contraceptive method (refer to the aforementioned) from the start of screening until two weeks of last dose administration to prevent his partner pregnant.
• Subjects agree to abstain from any prescription or non-prescription medications 2 weeks before the first dosing and throughout the study (except those allowed based on investigator's judgement).
• Have signed the written informed consent to participate in the study.

Exclusion criteria

• Clinically significant hepatic, renal, biliary, cardiovascular, gastrointestinal, haematological and other chronic and acute diseases within 3 months prior to the study.
• Clinically significant abnormality in physical examination, ECG evaluation, urine test, blood chemistry or haematological test.
• Tobacco uses in any forms.
• Positive results of hepatitis B.
• Regular consumer of alcohol (on average more than one drink per day within 1 month prior to the start of first dosing).
• Consumer of Asian vegetables, fruits or other herb medicine which are known to contain moderate to high levels of furanocoumarins, such as grapefruit juice, or herbal teas that naturally contain coumadin or coumadin-like substances such as Chamomile tea.
• Have lost or donate more than 350 ml blood donation within 4 weeks prior to the start of the study.
• Administer any prescription or non-prescription medications which is likely to be required during the course of the study (except those allowed based on investigator's judgement).
• Treatment of Gegen or the studied probe drugs (caffeine, losartan, omeprazole, metoprolol, midazolam, efavirenz) within 2 weeks before the study.
• Volunteer in any clinical drug study within 1 month prior to this study
• History of allergy or hypersensitivity to Gegen or the studied probe drugs (caffeine, losartan, omeprazole, metoprolol, midazolam, efavirenz) and other drugs in its class.
• History of drug abuse in any form.
• Genetics of the studied six CYPs revealed no enzyme activity (homozygous), including following genetic variants: CYP2C9*25, CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*35, CYP2D6*4, CYP2D6*6, CYP3A4*20.
• Female subjects who are breastfeeding or pregnancy.
• Subjects who are considered not suitable in participating the study due to other unfavourable factors determined by investigators.
• History or presence of problem in swallowing capsules and/or Chinese medicine.