How well do lipophilicity parameters, MEEKC microemulsion capacity factor, and plasma protein binding predict CNS tissue binding?

Journal of Pharmaceutical Sciences
Maciej J Zamek-GliszczynskiManuel Molina-Martin

Abstract

Brain fraction unbound (Fu) is critical to understanding the pharmacokinetics/dynamics of central nervous system (CNS) drugs, thus several surrogate predictors have been proposed. At present, correlations between brain Fu, microemulsion electrokinetic chromatography capacity factor (MEEKC k'), plasma Fu, octanol-water partition coefficient (clogP), and LogP at pH 7.4 (clogD(7.4) ) were compared for 94 diverse molecules, and additionally for 587 compounds. MEEKC k' was a better predictor of brain Fu (r(2) = 0.74) than calculated lipophilicity parameters (clogP r(2) = 0.51-0.54, clogD(7.4) r(2) = 0.41-0.44), but it was not superior to plasma Fu (r(2) = 0.74-0.85) as a predictor of brain Fu. MEEKC k' did not predict plasma Fu(r(2) = 0.58) as well as brain Fu, and the extent of improvement over clogP or clogD(7.4) (r(2) = 0.41-0.49) was less pronounced. Although log-log-correlation analysis supported seemingly strong prediction of brain Fu both by MEEKC k' and by plasma Fu (r(2) ≥ 0.74), analysis of prediction error estimated a 10-fold and 6.9-8.6-fold prediction interval for brain Fu estimated using MEEKC k' and plasma Fu, respectively. Therefore, MEEKC k' and plasma Fu can predict the log order of CNS tissue binding, but they can...Continue Reading

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Citations

Jan 9, 2013·Expert Opinion on Drug Metabolism & Toxicology·Kiril LanevskijRemigijus Didziapetris
Jun 20, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Maciej J Zamek-GliszczynskiJ William Higgins
Sep 30, 2016·Journal of Chemical Information and Modeling·Elena DolgikhThomas J Raub

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