Object: The authors evaluated convection-enhanced delivery (CED) of 14C-sucrose to the rat brain as a method of enhancing cerebral drug delivery and compared it with intravenous (i.v.) and intraventricular (i.v.t.) routes of administration.
Methods: Groups of rats received 14C-sucrose by bolus i.v. infusion, i.v.t. infusion for 1, 2, or 7 days at 0.17 microl/minute, or CED at rates from 0.01 to 0.5 microl/minute for periods from 1 hour to 7 days. Radioisotope distribution and concentration in tissue were analyzed using quantitative autoradiography. Intravenously administered sucrose reached the entire brain, but levels in tissue were low. After i.v.t. administration, sucrose levels in tissue were high at, and declined exponentially away from, the ventricular surface. Chronic CED administration maintained high levels of sucrose in tissue that focally were up to 10,000 times higher than in the i.v. group. The isotope distribution pattern after chronic CED infusions indicated a central component that resulted from convention and a peripheral component in gray matter that was the result of diffusion. The brain influx (0.42 microl/g/min) and diffusion constants of sucrose (2.8 x 10(-6) cm2/second) were similar to reported values. The total brain efflux constant was 0.0044 minute, whereas the blood-brain barrier (BBB) efflux constant was 0.0016 minute. There were no pathological changes in the brains after CED except those associated with cannula insertion. Sucrose, which was thought to be inert, was found to interact with brain tissue; up to 25% was bound to an unidentified tissue component.
Conclusions: Chronic CED appears to be a potentially useful method for significantly circumventing the BBB and increasing delivery of water-soluble drugs to the brain.