Clinical Evaluations of CYP 450 Inhibition and Anticoagulation Biomarker Alteration by Radix Puerariae Lobatae (Gegen): Impact on Its Potential Herb-drug Interactions
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- Change in CYP1A2 phenotypic activity
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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*
- •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.
研究组 & 干预措施
Low dose Gegen
Participants received the low-dose (3.3 g) Gegen regimen for 14 days; the six-probe drug cocktail was administered once before (Session I, baseline) and once after (Session II) Gegen dosing for CYP phenotyping.
干预措施: Arm 1: Radix Puerariae lobatae (Gegen) (Drug)
Low dose Gegen
Participants received the low-dose (3.3 g) Gegen regimen for 14 days; the six-probe drug cocktail was administered once before (Session I, baseline) and once after (Session II) Gegen dosing for CYP phenotyping.
干预措施: Arm 1: Six-probe drug cocktail (Drug)
High dose Gegen
Participants received the high-dose (5 g) Gegen regimen for 14 days; the six-probe drug cocktail was administered once before (Session I, baseline) and once after (Session II) Gegen dosing for CYP phenotyping.
干预措施: Arm 2: Radix Puerariae lobatae (Gegen) (Drug)
High dose Gegen
Participants received the high-dose (5 g) Gegen regimen for 14 days; the six-probe drug cocktail was administered once before (Session I, baseline) and once after (Session II) Gegen dosing for CYP phenotyping.
干预措施: Arm 2: Six-probe drug cocktail (Drug)
结局指标
主要结局
Change in CYP1A2 phenotypic activity
时间窗: Session I (baseline) and Session II (after 14 days of Gegen administration); within each session, blood samples collected at pre-dose (0 h) and 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 h after dosing of cocktail probe drugs.
Plasma concentrations of caffeine and its metabolite paraxanthine were quantified by validated LC-MS/MS. CYP1A2 activity was expressed as the AUC0-72 h derived metabolite-to-parent ratio (unit of measure: ratio).
Change in CYP2B6 phenotypic activity
时间窗: Session I (baseline) and Session II (after 14 days of Gegen administration); within each session, blood samples collected at pre-dose (0 h) and 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 h after dosing of cocktail probe drugs.
Plasma concentrations of efavirenz and its metabolite 8-Hydroxy-efavirenz were quantified by validated LC-MS/MS. CYP1A2 activity was expressed as the AUC0-72 h derived metabolite-to-parent ratio (unit of measure: ratio).
Change in CYP2C9 phenotypic activity
时间窗: Session I (baseline) and Session II (after 14 days of Gegen administration); within each session, blood samples collected at pre-dose (0 h) and 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 h after dosing of cocktail probe drugs.
Plasma concentrations of losartan and its metabolite E-3174 were quantified by validated LC-MS/MS. CYP1A2 activity was expressed as the AUC0-72 h derived metabolite-to-parent ratio (unit of measure: ratio).
Change in CYP2C19 phenotypic activity
时间窗: Session I (baseline) and Session II (after 14 days of Gegen administration); within each session, blood samples collected at pre-dose (0 h) and 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 h after dosing of cocktail probe drugs.
Plasma concentrations of omeprazole and its metabolite 5-Hydroxy-omeprazole were quantified by validated LC-MS/MS. CYP1A2 activity was expressed as the AUC0-72 h derived metabolite-to-parent ratio (unit of measure: ratio).
Change in CYP2D6 phenotypic activity
时间窗: Session I (baseline) and Session II (after 14 days of Gegen administration); within each session, blood samples collected at pre-dose (0 h) and 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 h after dosing of cocktail probe drugs.
Plasma concentrations of metoprolol and its metabolite α-Hydroxy-metoprolol were quantified by validated LC-MS/MS. CYP1A2 activity was expressed as the AUC0-72 h derived metabolite-to-parent ratio (unit of measure: ratio).
Change in CYP3A4 phenotypic activity
时间窗: Session I (baseline) and Session II (after 14 days of Gegen administration); within each session, blood samples collected at pre-dose (0 h) and 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 h after dosing of cocktail probe drugs.
Plasma concentrations of midazolam and its metabolite 1'-Hydroxy-midazolam were quantified by validated LC-MS/MS. CYP1A2 activity was expressed as the AUC0-72 h derived metabolite-to-parent ratio (unit of measure: ratio).
Change in thromboxane B2 concentration
时间窗: Blood samples collected at pre-dose (0 h) in Session I (baseline) and 72 hours post-cocktail-dose in Session II (after 14 days of Gegen dosing)
Plasma concentration of thromboxane B2, a biomarker of platelet activation and coagulation, was quantified by enzyme-linked immunosorbent assay (unit of measure: ng/mL).
Change in soluble thrombomodulin concentration
时间窗: Blood samples collected at pre-dose (0 h) in Session I (baseline) and 72 hours post-cocktail-dose in Session II (after 14 days of Gegen dosing)
Plasma concentration of soluble thrombomodulin, a biomarker of endothelial function, was quantified by enzyme-linked immunosorbent assay (unit of measure: ng/mL).
Change in prothrombin time
时间窗: Blood samples collected at pre-dose (0 h) in Session I (baseline) and 72 hours post-cocktail-dose in Session II (after 14 days of Gegen dosing)
Plasma prothrombin time, a coagulation parameter, was measured by standard clotting assay on an automated coagulometer (unit of measure: seconds).
次要结局
- Incidence of adverse events(From enrolment until the final visit (72 hours after the Session II probe cocktail administration))
研究者
Zhong Zuo
Professor
Chinese University of Hong Kong