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Pharmacodynamic and pharmacokinetic characterization of the aldosterone synthase inhibitor FAD286 in two rodent models of hyperaldosteronism: comparison with the 11{beta}-hydroxylase inhibitor metyrapone

Rigel, Dean and Fu, Fumin and Beil, Michael and Hu, Chii-Whei and Liang, Guiqing and Jeng, Arco (2010) Pharmacodynamic and pharmacokinetic characterization of the aldosterone synthase inhibitor FAD286 in two rodent models of hyperaldosteronism: comparison with the 11{beta}-hydroxylase inhibitor metyrapone. Journal of Pharmacology and Experimental Therapeutics, 334 (1). pp. 232-243. ISSN 0022-3565

Abstract

Aldosterone synthase (CYP11B2) inhibitors (ASI) represent an attractive therapeutic approach for mitigating the untoward effects of aldosterone. We characterized the pharmacokinetic/pharmacodynamic relationships of a prototypical ASI FAD286 (FAD) and compared these profiles to the "11beta-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 adrenocorticotropic hormone (ACTH, 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. ACTH but not ANG II elicited a sustained increase in plasma corticosterone concentration (PCC) from ~300 nM to ~1340 nM. After 1 h of Ang II or ACTH 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 ACTH 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 vs. 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 11beta-hydroxylase inhibitor.

Item Type: Article
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Additional Information: This MS was already approved as OAK ID#1823 but a glitch in the system did not allow me to progress. It has now been published as an Epub ahead of print
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2791

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