Pharmacokinetics and Pharmacodynamics of 4-Aminopyridine in Awake Guinea Pigs

Abstract

ABSTRACTThe selective blockade of potassium channels on excitable membranes by 4-aminopyridine (4-AP) leads to facilitation of neurotransmitter release at a wide variety of synapses. This compound has been shown to be efficacious against lethality induced by saxitoxin (STX) and tetrodotoxin (TTX) in guinea pigs. To characterize the actions of 4-AP in guinea pigs we have investigated its pharmacokinetics (PK) and pharmacodynamics following a 2 mg/kg, intramuscular (im) dose in awake chronically instrumented (IN) animals. Animals were chronically instrumented for electrophysiologic recordings of diaphragmatic electromyogram (DEMG), lead II electrocardiogram (ECGII) and electro-corticogram (ECoG). Also, PK studies were carried out in uninstrumented (UN) guinea pigs. Blood and electrophysiologic data were collected at predetermined time intervals up to 4 hours post 4-AP administration. High performance liquid chromatography was used to determine plasma 4-AP concentrations. For IN and UN animals, plasma concentration-time data best fit a one-compartment model, and PK parameter estimates were similar for both groups. Peak plasma levels were found to occur between 16 and 17 min, and the half-lives of elimination were 65 and 71 min for IN and UN animals respectively. Heart and respiratory rates were elevated as early as 5 and 15 min respectively in response to 4-AP administration. The duration of action was approximately 1–1.5 half-lives of elimination beyond peak plasma levels. Maximum ECoG responses were observed between 12–15 min after 4-AP injection; some residual drug effects were still apparent at 240 min. The difference between the heart and respiratory rates and ECoG profiles suggests that these different physiological systems respond with varying degrees of sensitivity to plasma 4-AP concentrations. The stimulation of these systems is consistent with the action of 4-AP in reversing STX- and TTX-induced cardiorespiratory depression and decreased ECoG power in guinea pigs.