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Abstract
Baclofen is a racemic mixture that is commonly used for the treatment for spasticity. However, the optimal dose and dosing interval to achieve effective cerebral spinal fluid (CSF) concentrations of baclofen are not known. Moreover, it is unclear if there are differences in the ability of R- or S-baclofen to cross the blood–brain barrier and achieve effective CSF concentrations. We have validated a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method with improved selectivity and sensitivity for the simultaneous quantitation of R- and S-baclofen and metabolites in plasma and CSF. Protein precipitation by acetonitrile was utilized to obtain an acceptable recovery of the analytes. The detection and separation of analytes was achieved on a 48 °C-heated Crownpak CR(+) column (150 mm × 4.0 mm, 5μ) with elution using 0.4% formic acid (FA) in water and 0.4% FA in acetonitrile as the mobile phase running at a flow rate of 1.0 mL/min. Accurate quantitation was assured by using this MS/MS method with atmospheric pressure chemical ionization in multiple reaction monitoring (MRM) mode. Therefore, this method is enantioselective, accurate, precise, sensitive, reliable, and linear from 1 to 1500 ng/mL for baclofen and 2 to 4000 ng/mL for the metabolites. An additional method was developed to separate racemic baclofen 3-(4-chlorophenyl)-4 hydroxybutyric acid metabolites for individual concentration determination. Both validated methods were successfully applied to a clinical pharmacokinetic human plasma and CSF study evaluating the disposition of baclofen and metabolites.
Highlights
Baclofen (4-amino-3-p-chlorophenyl butyric acid) (Figure 1) is a racemic mixture, comprising equal amounts of the R- and S-enantiomers and was initially designed as a treatment for seizures in the late 1960s
Positive and negative atmospheric pressure chemical ionization (APCI) and electrospray (ESI) conditions were tested for optimized MS conditions to detect baclofen and its metabolites
We have developed two reproducible and efficient LC-MS/MS methods for separating and quantitating racemic baclofen and its racemic CHBA metabolites, respectively
Summary
Baclofen (4-amino-3-p-chlorophenyl butyric acid) (Figure 1) is a racemic mixture, comprising equal amounts of the R- and S-enantiomers and was initially designed as a treatment for seizures in the late 1960s. Baclofen is the most commonly prescribed oral medication to treat spasticity of central origin [1,2], such as cerebral palsy [3], hemi- and tetraplegia [4], and multiple sclerosis [5]. Despite the widespread use of baclofen, substantial variability exists in exposure and clinical response even when patients receive similar doses of baclofen [6,7]. Molecules 2019, 24, x FOR PEER REVIEW Figure 1. The chemical chemical structure structure of of (a) baclofen, (b) baclofen-d4, and (c) 3-(4-chlorophenyl)-4 1.
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