Clinical trial NCT00872599: The Effect of a Peroxisome Proliferator-activated Receptor (PPAR) Alpha Agonist on Cytochrome P450 (CYP) Monooxygenase Activity in Humans
Official title: The Effect of a PPAR Alpha Agonist on CYP Monooxygenase Activity in Humans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypertension
Keywords: Hypertension
Phenotyping
High Salt intake
frequently sampled IV glucose tolerance test(FSIVGTT)
fenofibrate
epoxyeicosatrienoic acids
hydroxyeicosatetraenoic acids
dihydroxyeicosatrienoic acid
PPAR Alpha Agonist
CYP Monooxygenase Activity
Lead sponsor: Vanderbilt University
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
First posted: 2009-03-31
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

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-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.

Eligibility 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 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

Primary outcomes:
measure: Change in Blood Pressure During High Salt Intake and Fenofibrate Treatment Compared to High Salt Intake and Placebo Treatment
timeFrame: pressure measured on day 6 of high salt fenofibrate minus pressure measured on day 6 of high salt placebo
Secondary outcomes:
measure: HDL-cholesterol Measured During High Salt Fenofibrate in Salt-resistant and Salt-sensitive Hypertension
timeFrame: Measured on day 6 of high salt intake and fenofibrate treatment
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Nancy J Brown, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gilbert K, Nian H, Yu C, Luther JM, Brown NJ. Fenofibrate lowers blood pressure in salt-sensitive but not salt-resistant hypertension. J Hypertens. 2013 Apr;31(4):820-9. doi: 10.1097/HJH.0b013e32835e8227.
citation: Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28.