Durable pharmacological responses from the peptide ShK-186, a specific Kv1.3 channel inhibitor that suppresses T cell mediators of autoimmune disease

J Pharmacol Exp Ther. 2012 Sep;342(3):642-53. doi: 10.1124/jpet.112.191890. Epub 2012 May 25.

Abstract

The Kv1.3 channel is a recognized target for pharmaceutical development to treat autoimmune diseases and organ rejection. ShK-186, a specific peptide inhibitor of Kv1.3, has shown promise in animal models of multiple sclerosis and rheumatoid arthritis. Here, we describe the pharmacokinetic-pharmacodynamic relationship for ShK-186 in rats and monkeys. The pharmacokinetic profile of ShK-186 was evaluated with a validated high-performance liquid chromatography-tandem mass spectrometry method to measure the peptide's concentration in plasma. These results were compared with single-photon emission computed tomography/computed tomography data collected with an ¹¹¹In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugate of ShK-186 to assess whole-blood pharmacokinetic parameters as well as the peptide's absorption, distribution, and excretion. Analysis of these data support a model wherein ShK-186 is absorbed slowly from the injection site, resulting in blood concentrations above the Kv1.3 channel-blocking IC₅₀ value for up to 7 days in monkeys. Pharmacodynamic studies on human peripheral blood mononuclear cells showed that brief exposure to ShK-186 resulted in sustained suppression of cytokine responses and may contribute to prolonged drug effects. In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis, and pristane-induced arthritis rat models, a single dose of ShK-186 every 2 to 5 days was as effective as daily administration. ShK-186's slow distribution from the injection site and its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption / drug effects
  • Absorption / immunology
  • Animals
  • Arthritis / drug therapy
  • Arthritis / immunology
  • Arthritis / metabolism
  • Autoimmune Diseases / drug therapy*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • Cytokines / immunology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Kv1.3 Potassium Channel / antagonists & inhibitors*
  • Kv1.3 Potassium Channel / immunology
  • Kv1.3 Potassium Channel / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Macaca fascicularis
  • Potassium Channel Blockers / immunology
  • Potassium Channel Blockers / pharmacokinetics
  • Potassium Channel Blockers / pharmacology
  • Proteins / pharmacokinetics
  • Proteins / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Saimiri
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Tissue Distribution / drug effects
  • Tissue Distribution / immunology

Substances

  • Cytokines
  • Kv1.3 Potassium Channel
  • Potassium Channel Blockers
  • Proteins
  • Shk-186 peptide