Single- and repeated-dose pharmacokinetics of eplerenone, a selective aldosterone receptor blocker, in rats

• Published in: Xenobiotica Vol. 33; no. 3; pp. 305 - 321
• Main Authors: Cook, C. S., Zhang, L., Ames, G. B., Fischer, J., Zhang, J., Levin, S.
• Format: Journal Article
• Language: English
• Published: London Informa UK Ltd 01.03.2003; Taylor & Francis
• Subjects: Administration, Oral; Animals; Antihypertensive agents; Biological and medical sciences; Biotransformation; Cardiovascular system; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System - metabolism; Dose-Response Relationship, Drug; Eplerenone; Feces - chemistry; Female; Half-Life; In Vitro Techniques; Injections, Intravenous; Male; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Mineralocorticoid Receptor Antagonists - administration & dosage; Mineralocorticoid Receptor Antagonists - blood; Mineralocorticoid Receptor Antagonists - pharmacokinetics; Mixed Function Oxygenases - metabolism; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Sex Factors; Spironolactone - administration & dosage; Spironolactone - analogs & derivatives; Spironolactone - blood; Spironolactone - pharmacokinetics; Subcellular Fractions - metabolism; Intravenous administration; Rat; Mineralocorticoid; Rodentia; Single dose; Aldosterone; Metabolism; Multiple dose; Vertebrata; Mammalia; Eplerenone; Animal; Antihypertensive agent; Antagonist; Pharmacokinetics; Biological receptor
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/0049825021000049277

1. The pharmacokinetics of eplerenone (EP) were examined in rats following single or repeated dosing with 14 C-labelled or unlabelled EP to characterize absorption, metabolism and excretion. Rates of EP metabolism and cytochrome P450 activities were determined in vitro after repeated dose administration of EP. 2. Following a single i.v. dose (15 mg kg − 1), the elimination half-life of EP was 0.80 and 1.14 h in male and female rats, respectively. Plasma clearances (CL) of EP were 1.62 and 1.20 l kg − 1 h − 1 in males and females, respectively. Following a single oral dose (15 mg kg − 1), C max and T max of EP were 1.71 µg ml − 1 and 0.5 h in male rats. The corresponding values in female rats were 3.54 µg ml − 1 and 1.0 h. The systemic availability of EP was 25.6% in male rats and 66.4% in female rats, demonstrating sex differences in the pharmacokinetics of EP. 3. In the 8-day study, the AUC 0-24h 's of total EP (closed lactone ring form plus open form) following 100 and 200 mg kg − 1 oral doses were approximately half those on day 1 in male rats. After repeated dosing for 13 weeks, the pharmacokinetics of total EP did not change with study duration at the 20 mg kg − 1 dose in both males and females. However, at the 100 mg kg − 1 dose, AUC 0-24h 's were notably reduced on day 24 but progressively increased on subsequent days to approximate day 1 levels by day 86 in both sexes. At the 500 mg kg − 1 dose, the AUCs on day 86 remained lower than those on day 1. Reductions in AUCs on days 8 and 24 appeared to be the result of metabolism induction. 4. EP was extensively metabolized in male rats and most faecal and urinary radioactivity was in the form of metabolites. In female rats, the vast majority of urine and faecal radioactivity was associated with total EP. Thus, the sex difference in the pharmakokinetics of EP was due to more extensive metabolism in male rats. 5. The major metabolite in the rat was 6 β -OH EP. EP 6 β -hydroxylase activity was well correlated with testosterone 6 β -hydroxylase activity, indicating that EP metabolism to 6 β -OH EP was mediated primarily by CYP3A in the rat. 6. After repeated dose administration, EP increased 6 β -hydroxylase activities of testosterone and EP itself in a dose-dependent manner in both male and female rats, indicating that EP was a CYP3A inducer in the rat. There appeared to be no effects on activities of CYP1A1, 2B and 2E1.