MODELING THE ROUTE OF ADMINISTRATION-BASED ENHANCEMENT IN THE BRAIN DELIVERY OF EAB-515, STUDIED BY MICRODIALYSIS

EAB 515 amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid) is an extremely hydrophilic N-methyl-D-aspartate antagonist. It shows marke d CNS activity, in that it is a potent neuroprotector in models of cer ebral ischemia, and also demonstrates social and non-social behavioral alteration following systemic administration in animals. Because of i ts high degree of ionization at physiologic pH, one would not expect a ppreciable brain uptake of EAB 515 across tight junctions of the blood -brain barrier. This is in contrast to its pharmacologic effect as wel l as brain/plasma ratios measured during systemic administration in ra ts. These observations lead us to investigate other transport pathways that might account for its brain uptake, Such mechanistic information is imperative in rational drug delivery and drug design strategies. U pon intracerebroventricular administration, the observed steady-state cortical extracellular fluid concentrations of EAB 515 were over 100-f old higher than those observed following intravenous administration, w hen normalized for the dosing rate. This increased distribution into t he brain, based upon the route of administration, suggests the transpo rt of drug directly between the cerebrospinal fluid and the brain extr acellular space. The parameters of the model that adequately describes the data obtained from the two routes of administration in individual animals were estimated. The clinical significance of these results is in the use of intracerebroventricular administration for enhanced bra in delivery of hydrophilic drugs that poorly cross the blood-brain bar rier.