A chronic sheep preparation for the study of drug pharmacokinetics in spinal and ventricular CSF

We describe a sheep preparation utilizing chronic vascular and subarachnoid catheterization and ventriculocisternal perfusion. This preparation allows simultaneous, atraumatic sampling of plasma and CSF after drug administration by the intravenous, intracerebroventricular, or lumbar intrathecal (i.t.) routes in an unanesthesized animal. This sheep preparation provides a convenient means of studying the CSF distribution of exogenous and/or endogenous substances. During intravenous infusion at a rate of 2.2 micrograms/kg/min, morphine appears in cisternal CSF within 15 min. The steady-state plasma concentration and CSF flux (or appearance rate) of morphine was 0.037 and 0.009 micrograms/min, respectively. At steady state, 0.008% of the administered dose appears in CSF/min. The coadministration of morphine, methadone, and [14C]sucrose into the fifth lumbar subarachnoid space is associated with the simultaneous appearance of morphine and [14C]sucrose, but not methadone, in cisternal CSF. The ratio of [14C]sucrose to morphine increased by nearly sevenfold in cisternal CSF, indicating clearance of morphine relative to [14C]sucrose as the compounds ascend in the CSF axis. The simultaneous appearance of morphine and [14C]sucrose in cisternal CSF after lumbar subarachnoid administration indicates that morphine, like sucrose, is distributed within the CSF by bulk flow. This sheep preparation can be used to provide the quantitative data necessary for the development of pharmacokinetic-pharmacodynamic models that relate plasma and CSF concentrations of opiates to their pharmacological effects. These studies will help to provide the pharmacological rationale for the administration of opiates by novel routes for pain management in man.