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Pharmacokinetics and metabolism of SRX246: a potent and selective vasopressin 1a antagonist.
Fabio, Karine M; Guillon, Christophe D; Lu, Shi-Fang; Heindel, Ned D; Brownstein, Michael J; Lacey, Carl J; Garippa, Carrie; Simon, Neal G.
Afiliação
  • Fabio KM; Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015. Electronic address: karinefabio@msn.com.
  • Guillon CD; Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015; Azevan Pharmaceuticals, Inc., Bethlehem, Pennsylvania 18015.
  • Lu SF; Azevan Pharmaceuticals, Inc., Bethlehem, Pennsylvania 18015; Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015.
  • Heindel ND; Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015.
  • Brownstein MJ; Azevan Pharmaceuticals, Inc., Bethlehem, Pennsylvania 18015.
  • Lacey CJ; Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015.
  • Garippa C; Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015.
  • Simon NG; Azevan Pharmaceuticals, Inc., Bethlehem, Pennsylvania 18015; Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015.
J Pharm Sci ; 102(6): 2033-2043, 2013 Jun.
Article em En | MEDLINE | ID: mdl-23471831
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azetidinas / Antagonistas dos Receptores de Hormônios Antidiuréticos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azetidinas / Antagonistas dos Receptores de Hormônios Antidiuréticos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2013 Tipo de documento: Article