Abstract

Four pharmacologic actions of intravenous ketamine (30mg/kg) were studied in the rat. To elucidate the mechanism(s) terminating the pharmacologic effects, animals were pretreated with ketamine and agents anticipated to modify hepatic microsomal metabolism, including phenobarbital and SKF 525A. SKF 525A pretreatment markedly prolonged ataxia, analgesia and agitation, in addition to significantly elevating brain and plasms ketamine levels subsequent to the initial 10 minutes following injection; thus hepatic metabolism appeared to play a prominent role in the termination of the posthypnotic effects of the drug. While significantly shortening the durations of the three posthypnotic events, phenobarbital and ketamine pretreatments also lowered the brain and plasma levels of ketamine. With all pretreatments, brain ketamine levels were almost identical at the cessation of hypnosis (25 mug/g of tissue) and ataxia (8-10mug/g of tissue). No pretreatment altered either the duration of loss of righting reflex (hypnosis) or brain and plasma ketamine levels during the initial 10 minutes after injection. Approximately 70% of the injected drug was recovered from four tissues, skeletal muscle, gut, skin and liver, at 10 minutes after injection; thus redistribution from brain to other tissues appeared to play a major role in the cessation of hypnosis. Ketamine pretreatment caused a 2-fold increase in the rate of its in vitro hepatic microsomal metabolism. Brain and plasma ketamine levels 30 minutes after injection were nearly identical in rats pretreated with ketamine and phenobarbital, although phenobarbital pretreatment resulted in a 4-fold increase in in vitro ketamine hepatic metabolism.