Pharmacogenetics of Warfarin Induction and Inhibition
This research study will help determine how a person's genetic makeup affects their response to drugs, the ability of the body to break down drugs, and their potential to experience an interaction between drugs. The investigators are investigating the drug interactions with the commonly used anticoagulant drug called warfarin. Warfarin is used for the treatment and prevention of life-threatening abnormal blood clots such as deep vein thrombosis, heart attacks, and strokes. The investigators chose warfarin for this study because it is a commonly used drug and must be monitored closely to avoid side effects. The investigators are interested in studying whether individuals with certain genetic profiles react differently to warfarin when it is combined with other drugs. This research is being done to see if certain genetic profiles require us to adjust warfarin doses differently than is needed for the general population. Genetic profiles of subjects are determined from their participation in the Pharmacogenetics Registry study (investigator Richard Brundage, University of Minnesota).
The study hypothesis is: Functionally defective CYP2C9 alleles attenuate the warfarin-fluconazole inhibitory interaction and exacerbate the warfarin-rifampin inductive interaction.
調査の概要
詳細な説明
The research question is: How does CYP2C9 genotype modify warfarin drug interactions?
People differ in their genetic makeup. This includes differences in genes involved in drug metabolism, transport, and effect in the body. People with certain genetic profiles produce altered enzymes, transporters, and receptors that may respond in different ways to drugs. Altered enzymes cause some drugs to be broken down at a different rate than normal. As a result, drug concentrations build up in the blood, and increase the risk of side effects. Furthermore, when two drugs are taken together, the possibility exists for the drugs to interact, with one drug causing a change in the metabolism of the other or both of the drugs. It is not known whether people with an altered genetic makeup also have an altered experience with drug interactions. Altered drug transporters can affect the absorption and elimination of drugs as compared to normal causing differences in how long the drug stays in the body. Finally, altered drug receptors can respond differently to drugs and, thus, produce altered desired or undesired effects.
In this study, the investigators will be investigating the drug interactions with the commonly used anticoagulant drug warfarin in subjects with five different CYP2C9 genotypes. The CYP2C9 genotype is particularly important because this drug metabolizing enzyme governs the metabolic clearance of the more potent chemical entity (the S-enantiomer) of the drug. Warfarin is used for the treatment and prevention of life-threatening abnormal blood clots such as deep vein thrombosis, myocardial infarction, and strokes. The investigators chose warfarin for this study because it is a commonly used drug and must be monitored closely to avoid side effects. The investigators are interested in studying whether individuals with certain genetic alleles of the CYP2C9 genotype react differently to warfarin when it is combined with an antifungal (fluconazole) that inhibits CYP2C9-mediated metabolism and an antibiotic (rifampin) that induces CYP2C9-mediated metabolism. This research is being done to see if certain genetic profiles require us to adjust warfarin doses differently than is needed for the general population.
The study hypothesis is: Functionally defective CYP2C9 alleles attenuate the warfarin-fluconazole inhibitory interaction and exacerbate the warfarin-rifampin inductive interaction.
研究の種類
入学 (実際)
段階
- 適用できない
連絡先と場所
研究場所
-
-
Minnesota
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Minneapolis、Minnesota、アメリカ、55414
- Clinical and Translational Science Institute
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-
参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
- Subjects will be 18-60 years old.
- Women of child bearing age must be willing to use measures to avoid conception during the study period.
- Subjects must agree not to take any known substrates, inhibitors, inducers or activators of either CYP2C9 or CYP3A4 from 1 week prior to the start of each study through the last day of study.
Exclusion Criteria:
- Current cigarette smoker
- Abnormal renal, liver function tests, physical exam, or recent history of hepatic, renal, gastrointestinal or neoplastic disease.
- Allergy to warfarin, fluconazole or rifampin and other chemically related drugs.
- Recent ingestion (< 1 week) of any medication known to be metabolized by or alter CYP2C9 or CYP3A4 activity.
- A positive pregnancy test at the time of the pharmacokinetic study.
- Lab tests indicative of abnormal blood clotting capacity.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：基礎科学
- 割り当て：非ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
他の：CYP2C9*1/*1 Genotype
This genotype is considered the wild type genotype.
Individuals with the CYP2C9*1/*1 genotype have two *1 alleles and participated in the following interventions: Control - Warfarin only, Fluconazole - Warfarin, and Rifampin - Warfarin.
|
A single 10 mg warfarin dose taken at the start of the study period.
No other medications taken during this study period.
他の名前：
A single 10 mg warfarin dose taken at the start of the study period.
400 mg fluconazole taken every morning starting a week before the start of the study period and continuing throughout the study period.
他の名前：
A single 10 mg warfarin dose taken at the start of the study period.
300 mg rifampin taken every morning starting a week before the start of the study period and continuing throughout the study period.
他の名前：
|
|
他の：CYP2C9*1B/*1B Haplotype
Individuals with the CYP2C9*1B/*1B haplotype have two CYP2C9*1B alleles and participated in the following interventions: Control - Warfarin only and Rifampin - Warfarin.
|
A single 10 mg warfarin dose taken at the start of the study period.
No other medications taken during this study period.
他の名前：
A single 10 mg warfarin dose taken at the start of the study period.
300 mg rifampin taken every morning starting a week before the start of the study period and continuing throughout the study period.
他の名前：
|
|
他の：CYP2C9*1/*3 Genotype
Individuals with the CYP2C9*1/*3 genotype have one *1 allele and one *3 allele and participated in the following interventions: Control - Warfarin only, Fluconazole - Warfarin, and Rifampin - Warfarin.
|
A single 10 mg warfarin dose taken at the start of the study period.
No other medications taken during this study period.
他の名前：
A single 10 mg warfarin dose taken at the start of the study period.
400 mg fluconazole taken every morning starting a week before the start of the study period and continuing throughout the study period.
他の名前：
A single 10 mg warfarin dose taken at the start of the study period.
300 mg rifampin taken every morning starting a week before the start of the study period and continuing throughout the study period.
他の名前：
|
|
他の：CYP2C9*2/*3 Genotype
Individuals with the CYP2C9*2/*3 genotype have one *2 and one *3 allele and participated in the following interventions: Control - Warfarin only, Fluconazole - Warfarin, and Rifampin - Warfarin.
|
A single 10 mg warfarin dose taken at the start of the study period.
No other medications taken during this study period.
他の名前：
A single 10 mg warfarin dose taken at the start of the study period.
400 mg fluconazole taken every morning starting a week before the start of the study period and continuing throughout the study period.
他の名前：
A single 10 mg warfarin dose taken at the start of the study period.
300 mg rifampin taken every morning starting a week before the start of the study period and continuing throughout the study period.
他の名前：
|
|
他の：CYP2C9*3/*3 Genotype
Individuals with the CYP2C9*3/*3 genotype have two *3 alleles and participated in the following interventions: Control - Warfarin only, Fluconazole - Warfarin, and Rifampin - Warfarin.
|
A single 10 mg warfarin dose taken at the start of the study period.
No other medications taken during this study period.
他の名前：
A single 10 mg warfarin dose taken at the start of the study period.
400 mg fluconazole taken every morning starting a week before the start of the study period and continuing throughout the study period.
他の名前：
A single 10 mg warfarin dose taken at the start of the study period.
300 mg rifampin taken every morning starting a week before the start of the study period and continuing throughout the study period.
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Warfarin Clearance.
時間枠：Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods.
|
Warfarin enantiomer (S-warfarin and R-warfarin) clearance was measured in healthy volunteers genotyped for CYP2C9*1/*1, CYP2C9*1B/*1B, CYP2C9*1/*3, CYP2C9*2/*3 and CYP2C9*3/*3 to determine the magnitude of the warfarin-fluconazole (inhibition) and warfarin-rifampin (induction) drug interactions.
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Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods.
|
協力者と研究者
スポンサー
捜査官
- 主任研究者：Richard Brundage, PhD、University of Minnesota
出版物と役立つリンク
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
- 薬の生理作用
- 薬理作用の分子機構
- 抗感染剤
- 核酸合成阻害剤
- 酵素阻害剤
- ホルモン、ホルモン代替物、およびホルモン拮抗薬
- 抗菌剤
- シトクロム P-450 酵素阻害剤
- らい病剤
- ホルモン拮抗薬
- シトクロム P-450 酵素誘導剤
- 抗真菌剤
- 抗凝固剤
- ステロイド合成阻害剤
- シトクロム P-450 CYP3A インデューサー
- 抗結核剤
- 14-αデメチラーゼ阻害剤
- 抗生物質、抗結核薬
- シトクロム P-450 CYP2B6 インデューサー
- シトクロム P-450 CYP2C8 インデューサー
- シトクロム P-450 CYP2C19 インデューサー
- シトクロム P-450 CYP2C9 インデューサー
- シトクロム P-450 CYP2C9 阻害剤
- シトクロム P-450 CYP2C19 阻害剤
- リファンピン
- ワルファリン
- フルコナゾール
その他の研究ID番号
- 0807M38361
- P01GM032165-26 (米国 NIH グラント/契約)
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