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

Purpose: The purpose of this study is to understand how the traditional herbal medicine kudzu root (Gegen, Radix Puerariae lobatae) affects the activity of drug metabolizing enzymes in the body, and whether this could lead to interactions with other medicines. Background: Many medicines are broken down in the body by enzymes called cytochrome P450 (CYP) enzymes. Preclinical data suggest that Gegen can inhibit CYP enzymes, which may lead to herb-drug interactions; however, robust clinical evidence in humans remains insufficient. Participants: This study recruited 56 healthy Chinese adults, who were randomly assigned to parallel low and high dose Gegen groups; 52 participants finished the study. Interventions: Participants took a mixture of probe medicines known as a CYP probe cocktail to measure baseline CYP enzyme activity. After receiving either low or high dose Gegen, they received the probe cocktail again to detect changes in enzyme activity. Blood samples were collected to test the probe medicines, their breakdown products, and markers for blood clotting and blood vessel health. Outcome Measures: Primary outcomes include changes in blood levels and metabolic ratios of probe medicines. These values reflect differences in CYP enzyme activity with and without Gegen, and are compared across low and high dose groups. Hypothesis: The study hypothesized that Gegen alters CYP enzyme activity, and that the magnitude of this effect varies with Gegen dose.

Inclusion Criteria: 1. Male and non-pregnant female Chinese subjects, 20 - 45 years of age. 2. Body weight within 15% of ideal weight (according to the Metropolitan InsuranceCompany Bulletin). 3. Accessible vein for blood sampling. 4. High probability for compliance and completion of the study. 5. 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. 6. 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. 7. 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). 8. Have signed the written informed consent to participate in the study. Exclusion Criteria: 1. Clinically significant hepatic, renal, biliary, cardiovascular, gastrointestinal, haematological and other chronic and acute diseases within 3 months prior to the study. 2. Clinically significant abnormality in physical examination, ECG evaluation, urine test, blood chemistry or haematological test. 3. Tobacco uses in any forms. 4. Positive results of hepatitis B. 5. Regular consumer of alcohol (on average more than one drink per day within 1 month prior to the start of first dosing). 6. 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. 7. Have lost or donate more than 350 ml blood donation within 4 weeks prior to the start of the study. 8. 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). 9. Treatment of Gegen or the studied probe drugs (caffeine, losartan, omeprazole, metoprolol, midazolam, efavirenz) within 2 weeks before the study. 10. Volunteer in any clinical drug study within 1 month prior to this study 11. History of allergy or hypersensitivity to Gegen or the studied probe drugs (caffeine, losartan, omeprazole, metoprolol, midazolam, efavirenz) and other drugs in its class. 12. History of drug abuse in any form. 13. 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. 14. Female subjects who are breastfeeding or pregnancy. 15. Subjects who are considered not suitable in participating the study due to other unfavourable factors determined by investigators. 16. History or presence of problem in swallowing capsules and/or Chinese medicine.