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Metabolites 2012, 2(3), 596-613; doi:10.3390/metabo2030596
Article

Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans

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Received: 25 July 2012 / Revised: 21 August 2012 / Accepted: 29 August 2012 / Published: 11 September 2012
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Abstract

STX209 is an exploratory drug comprising the single, active R-enantiomer of baclofen which is in later stage clinical trials for the treatment of fragile x syndrome (FXS) and autism spectrum disorders (ASD). New clinical data in this article on the metabolism and pharmacokinetics of the R- and S-enantiomers of baclofen presents scientific evidence for stereoselective metabolism of only S-baclofen to an abundant oxidative deamination metabolite that is sterically resolved as the S-enantiomeric configuration. This metabolite undergoes some further metabolism by glucuronide conjugation. Consequences of this metabolic difference are a lower Cmax and lower early plasma exposure of S-baclofen compared to R-baclofen and marginally lower urinary excretion of S-baclofen after racemic baclofen administration. These differences introduce compound-related exposure variances in humans in which subjects dosed with racemic baclofen are exposed to a prominent metabolite of baclofen whilst subjects dosed with STX209 are not. For potential clinical use, our findings suggest that STX209 has the advantage of being a biologically defined and active enantiomer.
Keywords: pharmacokinetics; baclofen; R-baclofen; metabolic differentiation pharmacokinetics; baclofen; R-baclofen; metabolic differentiation
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Sanchez-Ponce, R.; Wang, L.-Q.; Lu, W.; von Hehn, J.; Cherubini, M.; Rush, R. Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans. Metabolites 2012, 2, 596-613.

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