RT Journal Article
SR Electronic
T1 Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 642
OP 653
DO 10.1124/jpet.112.191890
VO 342
IS 3
A1 Tarcha, Eric J.
A1 Chi, Victor
A1 Muñoz-Elías, Ernesto J.
A1 Bailey, David
A1 Londono, Luz M.
A1 Upadhyay, Sanjeev K.
A1 Norton, Kayla
A1 Banks, Amy
A1 Tjong, Indra
A1 Nguyen, Hai
A1 Hu, Xueyou
A1 Ruppert, Greg W.
A1 Boley, Scott E.
A1 Slauter, Richard
A1 Sams, James
A1 Knapp, Brian
A1 Kentala, Dustin
A1 Hansen, Zachary
A1 Pennington, Michael W.
A1 Beeton, Christine
A1 Chandy, K. George
A1 Iadonato, Shawn P.
YR 2012
UL http://jpet.aspetjournals.org/content/342/3/642.abstract
AB 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.