No abstract

Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensinconverting enzyme (ACE) inhibitors and angiotensin type 1 (AT 1 ) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels -a phenomenon termed "aldosterone synthesis escape." Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenonethe first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs) -is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding 185

This article is available online at http://dmd.aspetjournals.org ABSTRACT:A pharmacokinetics and metabolism study was conducted in eight healthy human volunteers. After oral administration of EP and its metabolites did not preferentially partition into the red blood cells and blood concentrations of total radioactivity were lower than plasma concentrations. Approximately 66.6% and 32.0% of the radioactive dose were excreted in urine and feces, respectively. The majority of urinary and fecal radioactivity was due to metabolites, indicating extensive metabolism of EP. The major metabolic pathways were 6␤-and/or 21-hydroxylation and 3-keto reduction. There was no evidence for any alteration of the 9,11-epoxide ring or the methyl ester. As a percentage of dose, the primary metabolic products excreted in urine and feces included 6␤-hydroxy-EP (6␤-OHEP) (32.0%), 6␤,21-OHEP (20.5%), 21-OHEP (7.89%), and 2␣,3␤,21-OHEP (5.96%). The amounts of the other metabolites excreted were less than 5% each.

Our findings suggest potential for PPi, administered during PD, to prevent the development of VC and to potentially extend the life of ESRD patients.

ABSTRACT:In vitro studies were conducted to identify the major metabolites of eplerenone (EP) and the cytochrome P450 (P450) isozymes involved in its primary oxidative metabolism in humans and dogs. The major in vitro metabolites were identified as 6␤-hydroxy EP and 21-hydroxy EP in both humans and dogs. EP was metabolized by cDNA-expressed human CYP3A4 and dog CYP3A12 but only minimally by human CYP3A5. In human microsomes, inhibition of total metabolism by the CYP3A-selective inhibitors ketoconazole, troleandomycin, and 6,7-dihydroxybergamottin, each at 10 M concentration, was 83 to 95%, whereas inhibition with inhibitors selective for other P450 isozymes was minimal. In dog liver microsomes, the percentages of inhibition were 53 to 76% with the CYP3A-selective inhibitors. A monoclonal anti-CYP3A4 antibody inhibited EP metabolism by 84%, whereas other monoclonal antibodies had minimal effects. The formation of 6␤-hydroxy and 21-hydroxy metabolites in human liver microsomes was best correlated with CYP3A-selective dextromethorphan N-demethylation and testosterone 6␤-hydroxylation activities. EP moderately inhibited only CYP3A (testosterone 6␤-hydroxylase) activity in human liver microsomes by 23, 34 and 45% at concentrations of 30, 100, and 300 M, respectively. With human microsomes, the V max and K m for 6␤-hydroxylation and 21-hydroxylation were 0.973 nmol/ min/mg and 217 M, and 0.143 nmol/min/mg and 211 M, respectively. The human hepatic clearance calculated from total in vitro EP metabolism was 2.30 ml/min/kg, which agrees with in vivo data. In conclusion, 6␤-and 21-hydroxylation of EP is primarily catalyzed by CYP3A4 in humans and CYP3A12 in dogs. Also, it is unlikely that EP would substantially inhibit the metabolism of other drugs that are metabolized by CYP3A4 or other P450 isoforms.