Modeling the route of administration-based enhancement in the brain delivery of EAB 515, studied by microdialysis

Journal of Drug Targeting
B K MalhotraR J Sawchuk

Abstract

EAB 515 (S-alpha-amino-5-phosphonomethyl[1,1'biphenyl]-3-propanoic acid) is an extremely hydrophilic N-methyl-D-aspartate antagonist. It shows marked CNS activity, in that it is a potent neuroprotector in models of cerebral ischemia, and also demonstrates social and non-social behavioral alteration following systemic administration in animals. Because of its high degree of ionization at physiologic pH, one would not expect appreciable brain uptake of EAB 515 across tight junctions of the blood-brain barrier. This is in contrast to its pharmacologic effect as well as brain/plasma ratios measured during systemic administration in rats. 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. Upon intracerebroventricular administration, the observed steady-state cortical extracellular fluid concentrations of EAB 515 were over 100-fold higher than those observed following intravenous administration, when normalized for the dosing rate. This increased distribution into the brain, based upon the route of administration, suggests the transport of drug directly between the cerebrospinal flu...Continue Reading

References

Mar 25, 1992·Analytical Chemistry·S MenacherryJ B Justice
Jun 1, 1973·The American Journal of Physiology·W H Oldendorf

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Citations

Jan 3, 2009·Ophthalmology·Suk Ho Byeon, Sung Yong Kang
May 1, 2007·Ophthalmology·Sophie J BakriRavinder J Singh
Jul 1, 2005·The Journal of Pharmacology and Experimental Therapeutics·Haiqing DaiWilliam F Elmquist

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