Pf. Morrison et al., HIGH-FLOW MICROINFUSION - TISSUE PENETRATION AND PHARMACODYNAMICS, The American journal of physiology, 266(1), 1994, pp. 180000292-180000305
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 v
olumetric 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 predict
ed concentration profile is relatively flat until it declines precipit
ously at the flow front. Hence, tissues are dosed rather uniformly, pr
oviding control over the undesired toxicity that may occur with altern
ative methods that depend on large concentration gradients for tissue
transport. The penetration advantage of high-flow (convective) over lo
w-flow (diffusive) microinfusion has been assessed at fixed pharmacody
namic effect. A 12-h high-flow microinfusion of a macromolecule degrad
ed with a characteristic time of 33.5 h would provide 5- to 10-fold in
creases in volume over low-flow infusion and total treatment volumes >
10 cm(3). Slower degradation rates would result in larger treatment v
olumes; 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 olig
onucleotides.