title: Pharmacokinetics and metabolism of SRX246: a potent and selective vasopressin 1a antagonist.
abstract: SRX246 is a potent, highly selective, orally bioavailable vasopressin 1a receptor antagonist that represents a novel mechanism of action for the treatment of mood disorders. The compound previously showed efficacy in animal models of mood disorders and excellent safety and tolerability in healthy volunteers in phase I clinical trials. In this study, SRX246 was further characterized in rats and dogs. In vitro determinations of permeability, protein binding, hepatocyte metabolism, and cytochrome P450 enzyme inhibition and in vivo assessments of pharmacokinetics were conducted. In parallel artificial membrane permeability assay (PAMPA) and PAMPA-blood-brain barrier models, SRX246 was comparable to highly permeable, orally active pharmaceuticals. SRX246 hydrochloride salt was 95.5 ± 1.7%, 95.9 ± 1.3%, and 98.6 ± 0.4% bound to rat, dog, and human serum proteins, respectively, and was stable in serum after a 4 h incubation at 37°C. P450 enzyme inhibition results showed a very low potential for drug-drug interactions. Metabolism in primary hepatocytes demonstrated that SRX246 was stable in humans and moderately metabolized in dogs and rats. Plasma pharmacokinetics findings showed a half-life (T½ ) of 2 and 6 h in rat and dog, respectively. Rat brain levels following a single oral dose were approximately 20% of plasma values with a T½ of 6 h. The observed profile for SRX246 supports further development.
authors.affiliation: Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015. Electronic address: karinefabio@msn.com.
authors.forename: Karine M
authors.initials: KM
authors.lastname: Fabio
authors.affiliation: Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015; Azevan Pharmaceuticals, Inc., Bethlehem, Pennsylvania 18015.
authors.forename: Christophe D
authors.initials: CD
authors.lastname: Guillon
authors.affiliation: Azevan Pharmaceuticals, Inc., Bethlehem, Pennsylvania 18015; Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015.
authors.forename: Shi-Fang
authors.initials: SF
authors.lastname: Lu
authors.affiliation: Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015.
authors.forename: Ned D
authors.initials: ND
authors.lastname: Heindel
authors.affiliation: Azevan Pharmaceuticals, Inc., Bethlehem, Pennsylvania 18015.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Brownstein
authors.affiliation: Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Lacey
authors.affiliation: Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015.
authors.forename: Carrie
authors.initials: C
authors.lastname: Garippa
authors.affiliation: Azevan Pharmaceuticals, Inc., Bethlehem, Pennsylvania 18015; Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015.
authors.forename: Neal G
authors.initials: NG
authors.lastname: Simon
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001384:Azetidines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D019964:Mood Disorders / Q000188:drug therapy; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001384:Azetidines; D001798:Blood Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; C584649:SRX246; D003577:Cytochrome P-450 Enzyme System