The Effect of a Peroxisome Proliferator-activated Receptor (PPAR) Alpha Agonist on Cytochrome P450 (CYP) Monooxygenase Activity in Humans

Study Overview
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Brief Summary
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The hypothesis is to test to see if the drug fenofibrate will increase important chemicals in the body and specifically in the kidney, help to rid the body of salt by the kidneys, decrease blood pressure and improve insulin sensitivity during high-salt intake in individuals with hypertension.

Detailed Description
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Hypertension affects 73 million people in the United States and a billion people worldwide and contributes to death due to stroke, myocardial infarction, end-stage kidney disease and congestive heart failure. Fifty to 60% of individuals with hypertension have salt-sensitive hypertension, characterized by an exaggerated blood pressure response to increased salt intake. Salt-sensitive hypertension is associated with increased mortality due to cardiovascular disease. This study will test the hypothesis that administration of a PPARa agonist, an intervention increases renal tubular Cyp2c and 4a expression in rodents, will increase urinary excretion of 20-hydroxyeicosatetraenoic acid(HETE) and epoxyeicosatrienoic acids(EET)s, induce natriuresis, decrease blood pressure, and improve insulin sensitivity during high-salt intake in individuals with hypertension. Metabolites of the P450 arachidonic acid monooxygenases play an important role in the regulation of blood pressure in rodent models. Targeted disruption of murine Cyp4a genes provides insight into the roles of renal monooxygenases and epoxygenases in the regulation of salt excretion and blood pressure. PPARa agonists induce the expression of renal tubular monoxygenases and epoxygenases and decrease blood pressure in both Ang II- dependent and salt-sensitive rodent models of hypertension. PPARa agonists have been reported to reduce blood pressure in clinical trials in humans. The effect of PPARa agonist on renal vasodilation, sodium excretion and excretion of urinary epoxygenase or monooxygenase products in response to salt loading is not known. The regulation of urinary 20-HETE excretion may be impaired in human hypertension.

Official Title
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The Effect of a PPAR Alpha Agonist on CYP Monooxygenase Activity in Humans

Conditions
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Hypertension

Intervention / Treatment
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* Drug: fenofibrate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ambulatory subjects, 18-70 years of age, inclusive For female subjects, the following conditions must be met Postmenopausal status for at least 1 year, or Status post surgical sterilization, or If of childbearing potential, utilization of adequate birth control and willingness to undergo urine beta-hcg testing prior to drug treatment and on every study day Exclusion Criteria: Secondary causes of hypertension Diabetes type 1 or type 2 as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication Use of hormone replacement therapy Statin or fibrate therapy A seated systolic blood pressure(SBP) greater than 179 mmHg or a seated diastolic blood pressure(DBP) greater than 110 mmHg Pregnancy Breast-feeding Cardiovascular disease such as history of myocardial infarction, presence of angina pectoris, significant arrhythmia, congestive heart failure, (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy Treatment with anticoagulants History of serious neurologic diseases such as cerebral hemorrhage,stroke, or transient ischemic attack History or presence of immunological or hematological disorders Diagnosis of asthma Clinically significant gastrointestinal impairment that could interfere with drug absorption Impaired hepatic function (aspartate aminotransferase [AST] and or alanine aminotransferase [ALT] > 2.0 x upper range) Known preexisting gallbladder disease Impaired renal function (eGFR < 60 ml/min/1.73M2) Hematocrit < 35% Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult Treatment with a glucocorticoid therapy Treatment with lithium salts History of of alcohol or drug abuse Treatment with any investigational drug in the 1 month preceding the study Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study Inability to comply with the protocol, e.g uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo, then fenofibrate<br>Randomized study of fenofibrate versus placebo during high salt diet | Drug: fenofibrate<br>* Subjects will be randomized to receive either fenofibrate 160 mg/day or matching placebo for five days by mouth.<br>* Other names: Tricor;Drug: Placebo<br>* Subjects will be randomized to receive placebo or fenofibrate for five days by mouth<br>|
| Placebo Comparator: Fenofibrate, then placebo<br>Randomized study of fenofibrate versus placebo during high salt intake. | Drug: fenofibrate<br>* Subjects will be randomized to receive either fenofibrate 160 mg/day or matching placebo for five days by mouth.<br>* Other names: Tricor;Drug: Placebo<br>* Subjects will be randomized to receive placebo or fenofibrate for five days by mouth<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Blood Pressure During High Salt Intake and Fenofibrate Treatment Compared to High Salt Intake and Placebo Treatment | Difference in blood pressure (mean arterial pressure) measured on the last day of high salt intake and fenofibrate treatment minus blood pressure (mean arterial pressure) measured during high salt intake and placebo treatment in participants classified as being salt-sensitive versus salt-resistant. Participants were classified as salt-sensitive if the average study day mean arterial pressure (MAP) was at least 5 mmHg higher during the high salt placebo arm than during low salt intake. | pressure measured on day 6 of high salt fenofibrate minus pressure measured on day 6 of high salt placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HDL-cholesterol Measured During High Salt Fenofibrate in Salt-resistant and Salt-sensitive Hypertension | HDL-cholesterol concentration measured on the last day of fenofibrate treatment in salt-resistant and salt-sensitive hypertensive patients | Measured on day 6 of high salt intake and fenofibrate treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PPAR Alpha Agonist, Hypertension, Phenotyping, High Salt intake, frequently sampled IV glucose tolerance test(FSIVGTT), fenofibrate, epoxyeicosatrienoic acids, hydroxyeicosatetraenoic acids, dihydroxyeicosatrienoic acid, CYP Monooxygenase Activity