Abstract
Aldosterone synthase (CYP11B2) inhibitors (ASIs) represent an attractive therapeutic approach for mitigating the untoward effects of aldosterone. We characterized the pharmacokinetic/pharmacodynamic relationships of a prototypical ASI, (+)-(5R)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl]benzonitrile hydrochloride (CGS020286A, FAD286, FAD) and compared these profiles to those of the 11β-hydroxylase inhibitor metyrapone (MET) in two rodent models of secondary hyperaldosteronism and corticosteronism. In chronically cannulated Sprague-Dawley rats, angiotensin II (ANG II) (300 ng/kg bolus + 100 ng/kg/min infusion) or adrenocorticotropin (100 ng/kg + 30 ng/kg/min) acutely elevated plasma aldosterone concentration (PAC) from ∼0.26 nM to a sustained level of ∼2.5 nM for 9 h. Adrenocorticotropin but not ANG II elicited a sustained increase in plasma corticosterone concentration (PCC) from ∼300 to ∼1340 nM. After 1 h of Ang II or adrenocorticotropin infusion, FAD (0.01–100 mg/kg p.o.) or MET (0.1–300 mg/kg p.o.) dose- and drug plasma concentration-dependently reduced the elevated PACs over the ensuing 8 h. FAD was ∼12 times more dose-potent than MET in reducing PAC but of similar or slightly greater potency on a plasma drug concentration basis. Both agents also decreased PCC in the adrenocorticotropin model at relatively higher doses and with similar dose potencies, whereas FAD was 6-fold weaker based on drug exposures. FAD was ∼50-fold selective for reducing PAC versus PCC, whereas MET was only ∼3-fold selective. We conclude that FAD is a potent, orally active, and relatively selective ASI in two rat models of hyperaldosteronism. MET is an order of magnitude less selective than FAD but is, nevertheless, more potent as an ASI than as an 11β-hydroxylase inhibitor.
Footnotes
This study was supported by Novartis Pharmaceuticals Corporation.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.167148.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- MR
- mineralocorticoid receptor
- MRA
- mineralocorticoid receptor antagonist
- AS
- aldosterone synthase
- ASI
- aldosterone synthase inhibitor
- FAD
- FAD286, (+)-(5R)-4-(5,6,7,8-tetrahydroimidazo [1,5-a]pyridin-5-yl]benzonitrile hydrochloride
- CGS020286A
- CGS016949A, fadrozole
- ANG II
- angiotensin II
- PK
- pharmacokinetic
- PD
- pharmacodynamic
- MET
- metyrapone
- PAC
- plasma aldosterone concentration
- PCC
- plasma corticosterone concentration
- SPA
- scintillation proximity assay
- PBS
- phosphate-buffered saline
- LC
- liquid chromatography
- MS/MS
- tandem mass spectroscopy
- AUC
- area under the concentration-time curve
- TWA
- time-weighted average
- LLOQ
- lower limit of quantification
- MOH
- metyrapol
- BAV
- bioavailability.
- Received February 9, 2010.
- Accepted March 29, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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