HIGH-FLOW MICROINFUSION - TISSUE PENETRATION AND PHARMACODYNAMICS

High-flow microinfusion provides a means for delivering macromolecules to large volumes of brain in easily obtainable time intervals. Slowly degraded similar to 180-kDa macromolecules, delivered at a constant volumetric flow rate of 3 mu l/min into homogeneous brain tissue (e.g., gray matter), would penetrate to a 1.5-cm radius in 12 h. The predicted concentration profile is relatively flat until it declines precipitously at the flow front. Hence, tissues are dosed rather uniformly, providing control over the undesired toxicity that may occur with alternative methods that depend on large concentration gradients for tissue transport. The penetration advantage of high-flow (convective) over low-flow (diffusive) microinfusion has been assessed at fixed pharmacodynamic effect. A 12-h high-flow microinfusion of a macromolecule degraded with a characteristic time of 33.5 h would provide 5- to 10-fold increases in volume over low-flow infusion and total treatment volumes > 10 cm(3). Slower degradation rates would result in larger treatment volumes; more rapid degradation rates would reduce the volume but still favor convective over diffusive administration. This technique may be applicable to a variety of diagnostic and therapeutic agents such as radioimmunoconjugates, immunotoxins, enzymes, growth factors, and oligonucleotides.