Due to limitations inherent in studies with patients, pharmacokinetic studies of morphine in monkeys are also being undertaken to elucidate information about the relationships between plasma and CSF morphine levels and between bolus and infusional administration of morphine. Serial plasma and CSF samples following single and multiple boluses and during constant drug infusions using doses comparable to those used in humans are being obtained. Samples are being analyzed for morphine using a commercial radioimmunoassay kit that provides a specific, sensitive and rapid method for the determination of morphine in biological samples. The pharmacokinetic data for single boluses has been obtained and studies utilizing multiple boluses and infusions are planned. In addition, the combination of X-rays of ifosfamide during morphine infusions will be studied to determine the basis for the observed increase in clinical toxicity with these combinations. The parmacokinetic data obtained from these studies will be analyzed by fitting the plasma pharmacokinetic data to a compartment model for morphine (2-COM) and by determining relationships between CSF and plasma data (AUC). The pharmacokinetic factors determined in this study may have important implications regarding the relationships between schedule and the effects of centrally acting drugs.
