In our previous research, cocaine applied intranasally in rats diffused or was transported directly from the nasal cavity to the brain. However, the direct nose-brain cocaine transport only contributes to an initial increase in the relative cocaine brain exposure. In this study, we have determined the 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 drainage of nasally applied dosing solution to non-nasal regions. Benzoylecgonine was then administered, either by intranasal administration or by intravenous (iv) injection. At different times postdose, blood and tissues from different regions of the brain were collected from groups of rats (n = 4 for each collection time) and benzoylecgonine concentrations in these samples were analyzed by high-performance liquid chromatography. Benzoylecgonine concentrations in plasma were at maximal levels immediately after iv dosing and declined as a function of time. Following intranasal administration, benzoylecgonine concentrations in plasma reached maximal levels between 15 and 30 min after dosing and declined as a function of time. To allow comparison of brain benzoylecgonine content after iv and intranasal administration, brain benzoylecgonine contents were normalized by-plasma benzoylecgonine concentrations. 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 dosing. The olfactory tract-to-plasma benzoylecgonine AUC ratios after intranasal administration were significantly higher than those after iv dosing up to 120 min following dosing. The brain tissue-to-plasma AUC ratios in cerebellum, brain stem, and cerebral cortex after intranasal administration were significantly higher than the corresponding ratios after iv administration up to 30 min following dosing. We conclude than nasally administered benzoylecgonine was transported directly from the nasal cavity to the brain and that the significant increase in brain levels was sustained for a prolonged period of time. Factors contributing to the observed differences in the nose-brain transport of cocaine and benzoylecgonine are discussed. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.
