Pharmacogenetics of Warfarin Induction and Inhibition
关键词
抽象
描述
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.
日期
最后验证: | 09/30/2018 |
首次提交: | 01/28/2010 |
提交的预估入学人数: | 10/03/2011 |
首次发布: | 10/05/2011 |
上次提交的更新: | 10/14/2018 |
最近更新发布: | 11/13/2018 |
首次提交结果的日期: | 07/29/2014 |
首次提交质量检查结果的日期: | 07/29/2014 |
首次发布结果的日期: | 08/17/2014 |
实际学习开始日期: | 04/30/2009 |
预计主要完成日期: | 05/31/2013 |
预计完成日期: | 05/31/2013 |
状况或疾病
干预/治疗
Drug: Control - Warfarin only
Drug: Fluconazole - Warfarin
Drug: Rifampin - Warfarin
相
手臂组
臂 | 干预/治疗 |
---|---|
Other: 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. | |
Other: 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. | |
Other: 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. | |
Other: 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. | |
Other: 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. |
资格标准
有资格学习的年龄 | 18 Years 至 18 Years |
有资格学习的性别 | All |
接受健康志愿者 | 是 |
标准 | 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. |
结果
主要结果指标
1. Warfarin Clearance. [Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods.]