Direct nose-brain transport of benzoylecgonine following intranasal administration in rats

In our previous research, cocaine applied intranasally in rats diffused or was transported directly from the nasal cavity to the brain. However, the d irect nose-brain cocaine transport only contributes to an initial increase in the relative cocaine brain exposure. In this study, we have determined t he nose-brain transport of a polar metabolite of cocaine, benzoylecgonine, to help understand factors affecting drug transport via this novel pathway. The nasal cavity of male Sprague-Dawley rats was isolated to prevent drain age of nasally applied dosing solution to non-nasal regions. Benzoylecgonin e was then administered, either by intranasal administration or by intraven ous (iv) injection. At different times postdose, blood and tissues from dif ferent regions of the brain were collected from groups of rats (n = 4 for e ach collection time) and benzoylecgonine concentrations in these samples we re analyzed by high-performance liquid chromatography. Benzoylecgonine conc entrations in plasma were at maximal levels immediately after iv dosing and declined as a function of time. Following intranasal administration, benzo ylecgonine concentrations in plasma reached maximal levels between 15 and 3 0 min after dosing and declined as a function of time. To allow comparison of brain benzoylecgonine content after iv and intranasal administration, br ain benzoylecgonine contents were normalized by-plasma benzoylecgonine conc entrations. The ratios of the area under the benzoylecgonine concentration- time curve (AUC) between the olfactory bulb and plasma following intranasal administration were 10-100 times higher than those obtained after iv dosin g. The olfactory tract-to-plasma benzoylecgonine AUC ratios after intranasa l administration were significantly higher than those after iv dosing up to 120 min following dosing. The brain tissue-to-plasma AUC ratios in cerebel lum, brain stem, and cerebral cortex after intranasal administration were s ignificantly higher than the corresponding ratios after iv administration u p to 30 min following dosing. We conclude than nasally administered benzoyl ecgonine was transported directly from the nasal cavity to the brain and th at the significant increase in brain levels was sustained for a prolonged p eriod of time. Factors contributing to the observed differences in the nose -brain transport of cocaine and benzoylecgonine are discussed. (C) 2001 Wil ey-Liss, Inc. and the American Pharmaceutical Association.