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Non-specific quantitation of [14C]sucrose in blood and brain has been routinely used as a quantitative measure of the in vivo blood-brain barrier (BBB) integrity. However, the reported apparent brain uptake clearance (Kin) of the marker varies widely (∼100 fold). We investigated the accuracy of the use of the marker in comparison with a stable isotope of sucrose ([13C]sucrose) measured by a specific LC-MS/MS method. Rats received single doses of each marker, and the Kin values were determined. Surprisingly, the Kin value of [13C]sucrose was 6-7 fold lower than that of [14C]sucrose. Chromatographic fractionation after in vivo administration of [14C]sucrose indicated that the majority of the brain content of radioactivity belonged to compounds other than the intact [14C]sucrose. However, mechanistic studies failed to reveal any substantial metabolism of the marker. The water: octanol partition coefficient of [14C]sucrose was > 2 fold higher than that of [13C]sucrose, indicating presence of lipid-soluble impurities in the [14C]sucrose solution. Our data indicate that [14C]sucrose overestimates the true BBB permeability to sucrose. We suggest that specific quantitation of the stable isotope (13C) of sucrose is a more accurate alternative to the current widespread use of the radioactive sucrose as a BBB marker.


NOTICE: this is the author’s version of a work that was accepted for publication in Journal of Pharmaceutical Sciences. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Pharmaceutical Sciences in 2017. DOI: 10.1016/j.xphs.2017.02.011

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