Pharmacodynamic and Pharmacokinetic Characterization of the Aldosterone Synthase Inhibitor FAD286 in Two Rodent Models of Hyperaldosteronism: Comparison with the 11β-Hydroxylase Inhibitor Metyrapone

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, (ϩ)-(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 11␤-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 ϩ 100 ng/kg/ min infusion) or adrenocorticotropin (100 ng/kg ϩ 30 ng/kg/ min) acutely elevated plasma aldosterone concentration (PAC) from ϳ0.26 nM to a sustained level of ϳ2.5 nM for 9 h. Adrenocorticotropin but not ANG II elicited a sustained increase in plasma corticosterone concentration (PCC) from ϳ300 to ϳ1340 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.) doseand drug plasma concentration-dependently reduced the elevated PACs over the ensuing 8 h. FAD was ϳ12 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 ϳ50-fold selective for reducing PAC versus PCC, whereas MET was only ϳ3-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 11␤-hydroxylase inhibitor.

Aldosterone Synthase Inhibition With LCI699

“…These data are in agreement with a recent study, which shows that FAD286 is Ϸ50-fold more selective at reducing plasma aldosterone than plasma cortisol concentrations, whereas the 11␤-hydroxylase inhibitor metyrapone is only Ϸ3-fold more selective in rodent models of secondary hyperaldosteronism and corticosteronism. 36 The presence of a mild reversible impairment in cortisol synthesis during LCI699 treatment had no clinical or biological adverse consequences in the short-term study, and all of the patients recovered normal glucocorticoid adrenal function after LCI699 was stopped for a week. However, the longterm effects of suppressing the adrenal response, particularly in response to stressful situations and those of a 2-fold increase in plasma ACTH on adrenal steroid synthesis and tissue changes, are unknown.…”

Neovascularization Is Attenuated With Aldosterone Synthase Inhibition in Rats With Retinopathy

“…FAD286 is a relatively selective aldosterone synthase inhibitor that is 50 times more selective for reducing plasma aldosterone concentration than plasma corticosterone. 31 The finding that FAD286 reduced retinal neovascularization and inflammation in OIR with a concomitant reduction in retinal aldosterone synthase mRNA suggested that the effects of FAD286 were attributed to a reduction of retinal aldosterone production. However, a limitation of our study was that we cannot comment on whether FAD286 influenced local production of aldosterone, because retinal aldosterone levels were not measured because of the small size of the neonatal retina.…”

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

“…Although it is a potent and relatively selective inhibitor of 11b-hydroxylase, it also inhibits 18-hydroxylase (Fig. 1), and recent in vitro data indicate that overall it has greater inhibitory action on aldosterone synthase, a feature not previously recognised (45). Oral administration of metyrapone results in a significant and reversible reduction in cortisol and aldosterone production (46).…”