The Effect of a Peroxisome Proliferator-Activated Receptor (PPAR) Alpha Agonist on Cytochrome P450 (CYP) Monooxygenase Activity in Humans
Information source: Vanderbilt University
Information obtained from ClinicalTrials.gov on October 19, 2009
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hypertension
Intervention: fenofibrate (Drug); Placebo (Drug)
Phase: Phase 1
Status: Not yet recruiting
Sponsored by: Vanderbilt University Official(s) and/or principal investigator(s):
Nancy J Brown, MD, Principal Investigator, Affiliation: Vanderbilt University
Overall contact:
Loretta Byrne, MSN, Phone: 615-322-2105, Email: loretta.byrne@vanderbilt.edu
Summary
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.
Clinical Details
Official title: The Effect of a PPAR Alpha Agonist on CYP Monooxygenase Activity in Humans
Study design: Treatment, Randomized, Double Blind (Subject, Investigator), Crossover Assignment, Pharmacokinetics Study
Primary outcome: Focus on the effects of fenofibrate during high-salt intake on blood pressure twenty-four hour 20-HETE, EET and DHET excretion, renal blood flow and net sodium excretion and Aldosterone to renin ratio.
Secondary outcome: Focus on the effect of fenofibrate on insulin sensitivity, glucose effectiveness, beta cell function and HDL-cholesterol.
Detailed description:
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-HETE and EETs, 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.
Eligibility
Minimum age: 18 Years.
Maximum age: 70 Years.
Gender(s): Both.
Criteria:
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 SBP greater than 179 mmHg or a seated 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 amino transaminase [AST] and or alanine amino
transaminate [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
Locations and Contacts
Loretta Byrne, MSN, Phone: 615-322-2105, Email: loretta.byrne@vanderbilt.edu
Vanderbilt University, Nashville, Tennessee 37232, United States
Additional Information
Starting date: July 2009
Ending date: July 2011
Last updated: March 30, 2009
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