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
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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.
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(3):596-613.
Sanchez-Ponce, Raymundo; Wang, Li-Quan; Lu, Wei; von Hehn, Jana; Cherubini, Maryann; Rush, Roger. 2012. "Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans." Metabolites 2, no. 3: 596-613.