Pharmacokinetics, toxicity, and functional studies of the selective Kv1.3 channel blocker 5-(4-phenoxybutoxy)psoralen in rhesus macaques.

Abstract

The small molecule 5-(4-phenoxybutoxy)psoralen (PAP-1) 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 (TEMs). The blockade of Kv1.3 results in membrane depolarization and inhibition of TEM proliferation and function. In this study, the in vitro effects of PAP-1 on T cells and the in vivo toxicity and pharmacokinetics (PK) were examined in rhesus macaques (RM) with the ultimate aim of utilizing PAP-1 to define the role of TEMs in RM infected with simian immunodeficiency virus (SIV). Electrophysiologic studies on T cells in RM revealed a Kv1.3 expression pattern similar to that in human T cells. Thus, PAP-1 effectively suppressed TEM proliferation in RM. When administered intravenously, PAP-1 showed a half-life of 6.4 hrs; the volume of distribution suggested extensive distribution into extravascular compartments. When orally administered, PAP-1 was efficiently absorbed. Plasma concentrations in RM undergoing a 30-day, chronic dosing study indicated that PAP-1 levels suppressive to TEMs in vitro can be achieved and maintained in vivo at a non-toxic dose. PAP-1 selectively inhibited the 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 (flu) virus suggested 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.