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Sanchez-Ponce R, Wang LQ, Lu W, et al. Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans. Metabolites. 2012;2(3):596-613doi: 10.3390/metabo2030596.
Sanchez-Ponce, R., Wang, L. Q., Lu, W., von Hehn, J., Cherubini, M., & Rush, R. (2012). Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans. Metabolites, 2(3), 596-613. https://doi.org/10.3390/metabo2030596
Sanchez-Ponce, Raymundo, et al. "Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans." Metabolites vol. 2,3 (2012): 596-613. doi: https://doi.org/10.3390/metabo2030596
Sanchez-Ponce R, Wang LQ, Lu W, von Hehn J, Cherubini M, Rush R. Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans. Metabolites. 2012 Sep 11;2(3):596-613. doi: 10.3390/metabo2030596. PMID: 24957649; PMCID: PMC3901214.
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Metabolites. 2012 Sep 11;2(3):596-613. doi: 10.3390/metabo2030596.

Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans.

Metabolites

Raymundo Sanchez-Ponce, Li-Quan Wang, Wei Lu, Jana von Hehn, Maryann Cherubini, Roger Rush

Affiliations

  1. Seaside Therapeutics, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA. [email protected].
  2. XenoBiotic Laboratories, Inc., 107 Morgan Lane, Plainsboro, NJ 08536, USA. [email protected].
  3. XenoBiotic Laboratories, Inc., 107 Morgan Lane, Plainsboro, NJ 08536, USA. [email protected].
  4. Seaside Therapeutics, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA. [email protected].
  5. Seaside Therapeutics, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA. [email protected].
  6. Seaside Therapeutics, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA. [email protected].

PMID: 24957649 PMCID: PMC3901214 DOI: 10.3390/metabo2030596

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.

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