Pharmacodynamic and pharmacokinetic characterization of the aldosterone synthase inhibitor FAD286 in two rodent models of hyperaldosteronism: comparison with the 11beta-hydroxylase inhibitor metyrapone.
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 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 adrenocorticotropin (100 ng/kg + 30 ng/kg/min) acutely elevated plasma aldosterone concentration (PAC) from approximately 0.26 nM to a sustained level of approximately 2.5 nM for 9 h. Adrenocorticotropin but not ANG II elicited a sustained increase in plasma corticosterone concentration (PCC) from approximately 300 to approximately 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 approximately 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 approximately 50-fold selective for reducing PAC versus PCC, whereas MET was only approximately 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.
Rigel
Dean F
DF
Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936-1080, USA. dean.rigel@novartis.com
Fu
Fumin
F
Beil
Michael
M
Hu
Chii-Whei
CW
Liang
Guiqing
G
Jeng
Arco Y
AY
D000311:Adrenal Glands / Q000187:drug effects* / Q000201:enzymology; D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D002853:Chromatography, Liquid; D003345:Corticosterone / Q000097:blood; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D017316:Fadrozole; D006929:Hyperaldosteronism / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D008797:Metyrapone / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D017316:Fadrozole; D003345:Corticosterone; D008797:Metyrapone