Pharmacokinetics and Pharmacodynamics of 4-Aminopyridine in Awake Guinea Pigs

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 concen...