Pharmacokinetics, Toxicity, and Functional Studies of the Selective Kv1.3 Channel Blocker 5-(4-Phenoxybutoxy)Psoralen in Rhesus Macaques

• Authors: L. E. Pereira, Emory University; Francois Villinger, Emory University; H. Wulff, University of California Davis; A. Sankaranarayanan, University of California Davis; G. Raman, University of California Davis; Aftab A Ansari, Emory University
• Journal Title: Experimental Biology and Medicine
• Volume: Volume 232, Number 10
• Publisher: SAGE Publications (UK and US) | 2007-11, Pages 1338-1354
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.3181/0705-RM-148
• Subjects: Health Sciences, Pharmacology; Health Sciences, Pathology; Biology, Cell
• Keywords: effector memory T-cells; SIV; PAP-1; K+ channel blockers

Abstract

The small molecule PAP-1 (5-(4-phenoxybutoxy)psoralen) is a selective blocker of the voltage-gated potassium channel Kv1.3 that is highly expressed in cell membranes of activated effector memory T-cells (TEM). The blockade of Kv1.3 results in membrane depolarization and inhibition of TEM cell proliferation and function. In this study, the in vitro effects of PAP-1 on rhesus macaques (RM) T cells and the in vivo toxicity and pharmacokinetics (PK) were examined in RM with the ultimate aim of utilizing PAP-1 to define the role of TEM in RM infected with simian immunodeficiency virus (SIV). Electrophysiological studies on RM T-cells revealed a Kv1.3 expression pattern similar to that in human T-cells. Thus, PAP-1 effectively suppressed RM TEM cell proliferation. Intravenously administered PAP-1 showed a half-life of 6.4 hrs and the volume of distribution suggested that it is distributed extensively into extravascular compartments. Orally administered PAP-1 was efficiently absorbed and plasma concentrations in RM undergoing a 30-day chronic dosing study indicated that PAP-1 levels that are suppressive to TEM cells in vitro can be achieved and maintained in vivo at a non-toxic dose. PAP-1 selectively inhibited TEM function in vivo as indicated by a modest reactivation of cytomegalovirus (CMV) replication. Immunization of these chronically-treated RM with the live influenza A/PR8 virus suggest that the development of an in vivo flu-specific central memory response was unaffected by PAP-1. These RM remained disease-free during the entire course of the PAP-1 study. Collectively these data provide a rational basis for future studies with PAP-1 in SIV-infected RM.