title: Rhesus monkey model for concurrent analyses of in vivo selectivity, pharmacokinetics and pharmacodynamics of aldosterone synthase inhibitors.
abstract: BACKGROUND
  In vivo profiles of aldosterone synthase inhibitors (ASIs) have been investigated utilizing various rodent models. Due to lack of CYP17 activity, rodents produce corticosterone rather than cortisol as that of humans, which raised concern to their effectiveness in translational pharmacological characterization of ASI.
  
  
  METHODS
  A rhesus monkey model that combines a low sodium diet with adrenocorticotropin (ACTH) treatment was developed. Plasma concentrations of steroid metabolites associated with reactions catalyzed by CYP11B2 and CYP11B1 were measured concurrently by a UPLC/MS method.
  
  
  RESULTS
  Plasma concentration of aldosterone in regular diet fed rhesus monkeys was low at 109pg/mL. Aldosterone concentrations were increased to 252pg/mL when animals were maintained on a low sodium diet for 3weeks, and to 300pg/mL with ACTH treatment at 0.3mg/kg. The combination of low sodium diet with ACTH treatment further increased plasma concentration of aldosterone to 730pg/mL and other steroid metabolites at various levels. Intravenous administration of ASI, fadrozole (0.001-1mg/kg) or LCI699 (0.003-3mg/kg), led to dose-dependent reductions in aldosterone and 18-hydroxycorticosterone, increases in 11-deoxycorticosterone and 11-deoxycortisol, and bell-shaped changes in cortisol and corticosterone. In vivo selectivity of CYP11B2/CYP11B1 for fadrazole was 26-fold and LCI-699 was 27-fold, which was consistent with relative selectivity using in vitro values from recombinant cells transfected with rhesus monkey CYP11B2 and CYP11B1.
  
  
  CONCLUSIONS
  This model enables concurrent characterization of pharmacokinetics, pharmacodynamics and selectivity of CYP11B2 over CYP11B1 inhibition in the same animal. It may be used as a translational model for pharmacological characterization of ASI.
authors.affiliation: In Vivo Pharmacology, Kenilworth, NJ, USA. Electronic address: tianquan_cai@merck.com.
authors.forename: Tian-Quan
authors.initials: TQ
authors.lastname: Cai
authors.affiliation: In Vivo Pharmacology, Kenilworth, NJ, USA.
authors.forename: Sloan
authors.initials: S
authors.lastname: Stribling
authors.affiliation: Pharmacokinetics and Drug Metabolism, Kenilworth, NJ, USA.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.affiliation: Pharmacokinetics and Drug Metabolism, Kenilworth, NJ, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Cardiovascular Diseases of Merck Research Laboratories, Kenilworth, NJ, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
authors.affiliation: New Iberia Primate Research Center, New Iberia, LA, USA.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Fontenot
authors.affiliation: Cardiovascular Diseases of Merck Research Laboratories, Kenilworth, NJ, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Struthers
authors.affiliation: Cardiovascular Diseases of Merck Research Laboratories, Kenilworth, NJ, USA.
authors.forename: Karen O
authors.initials: KO
authors.lastname: Akinsanya
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008297:Male; D023421:Models, Animal; D012982:Sodium, Dietary / Q000008:administration & dosage / Q000493:pharmacokinetics; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013256:Steroids / Q000097:blood / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D012982:Sodium, Dietary; D013256:Steroids; D000324:Adrenocorticotropic Hormone; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase
keywords: Aldosterone; Animal model; Glucocorticoids; Pharmacodynamics; Pharmacokinetics