Ultrasensitive quantification of the CYP2E1 probe chlorzoxazone and its main metabolite 6-hydroxychlorzoxazone in human plasma using ultra performance liquid chromatography coupled to tandem mass spectrometry after chlorzoxazone microdosing

Witt, Lukas; Suzuki, Yosuke; Hohmann, Nicolas; Mikus, Gerd; Haefeli, Walter E.; Burhenne, Jürgen

doi:10.1016/j.jchromb.2016.05.049

Cited by 16 publications

(8 citation statements)

References 25 publications

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“…Our results support the view that molecules acting as BKCa agonists may be a valid therapeutic strategy for FXS, i.e., an idea that we have already proposed in previous studies in Fmr1-KO mice, where we demonstrated that the acute administration of BMS, another BKCa channel opener, was able to eliminate several behavioural abnormalities in FXS mice (Carreno-Munoz et al , 2018, Hebert et al , 2014, Zhang et al , 2014), as well as their hippocampal dendritic alterations (Hebert et al , 2014) and cortical hyper-excitability (Zhang et al , 2014). Nonetheless, CHLOR seems a more valuable therapeutic agent for clinical application than BMS, as the latter suffers from limited efficacy in chronic protocols of administration and short half-life (Hebert et al , 2014), i.e., two problems that do not affect CHLOR (Hohmann et al , 2019, Witt et al , 2016). The comparison between CHLOR and other two treatments recently proposed for FXS further strengthens the value of this molecule as a treatment for FXS; here, we could not detect any acute behavioural effect of MET, in agreement with previous reports on the Fmr1-KO model (Gantois et al , 2017), and we found limited chronic effects of MET, i.e., on repetitive behaviours and, more slightly, on social deficits (Fig.2-B and –C), that were largely less marked than those induced by chronic CHLOR.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome

Lemaire-Mayo

Piquemal

Crusio

et al. 2020

Preprint

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Fragile X syndrome (FXS) is an X-linked developmental disorder characterized by several behavioral abnormalities, including hyperactivity, sensory hyper-responsiveness and cognitive deficits, as well as autistic symptoms, e.g., reduced social interaction. These behavioural alterations are recapitulated by the major animal model of FXS, i.e., the Fmr1-KO mouse, which has been extensively employed to identify therapeutic targets for FXS, though effective pharmacological treatments are still lacking. Here we focused on the therapeutic role of large-conductance Calcium-dependent potassium (BKCa) channels, playing a crucial role in neuronal excitability and neurotransmitter release. Reduced expression/functionality of these channels has been described in FXS patients and mice, so that molecules activating these channels have been proposed as promising treatments for this syndrome. Here we performed an extensive characterization of the therapeutic impact of a novel BKCa agonist on FXS-like symptoms in the Fmr1-KO mouse model, employing a drug repurposing setting. We evaluated the acute and chronic effects of chlorzoxazone, i.e., a classical drug used for non-developmental muscular pathologies, on the locomotor, social, cognitive and sensory-motor alterations of Fmr1-KO mice and compared them with other pharmacological treatments recently proposed for FXS that instead do not target BKCa channels. Our results clearly demonstrate for the first time the marked efficacy of chlorzoxazone in treating all the behavioral abnormalities of FXS mice, thus encouraging the preferential use of this molecule over others for clinical applications in the field of FXS, and potentially of other neurodevelopmental disorders.

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Section: Discussionmentioning

confidence: 99%

Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome

Lemaire-Mayo

Piquemal

Crusio

et al. 2020

Preprint

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“…3) data for more than one subject was reported. Data from (Bedada and Neerati, 2016;Bedada and Boga, 2017;Bedada and Neerati, 2018;Benowitz et al, 2003;Burckart et al, 1998;Chalasani et al, 2003;Dreisbach et al, 1995;Eap et al, 1998;Girre et al, 1994;He et al, 2019;de la Maza et al, 2000;Liangpunsakul et al, 2005;Lucas et al, 1993;Park et al, 2006;Rajnarayana et al, 2008;Vesell et al, 1995;Wang et al, 2003;Hohmann et al, 2019;Witt et al, 2016). (B, C) Time course data from (Girre et al, 1994;Lucas et al, 1993) for non-drinking control (black dashed line) and alcoholic subjects (red solid line).…”

Section: Discussionmentioning

confidence: 99%

“…Our model successfully described the concentration profiles of chlorzoxazone, 6-hydroxychlorzoxazone, chlorzoxazone-O-glucuronide, and the amount of chlorzoxazone-O-glucuronide excreted in the urine over time. The model was able to predict these profiles for doses ranging from 0.005 mg to 750 mg administered as tablets or oral solutions in the studies we used for model parameterization (Bedada and Neerati, 2016;Bedada and Boga, 2017;Bedada and Neerati, 2018;Burckart et al, 1998;de Vries et al, 1994;Dreisbach et al, 1995;Frye et al, 1998;Girre et al, 1994;He et al, 2019;de la Maza et al, 2000;Liangpunsakul et al, 2005;Lucas et al, 1993;Park et al, 2006;Rajnarayana et al, 2008;Vesell et al, 1995;Wang et al, 2003;Hohmann et al, 2019;Witt et al, 2016). Refer to Tab.…”

Section: Model Performancementioning

confidence: 99%

“…Studies were selected when they met the following criteria: (1) only chlorzoxazone was administered (no cocktail or co-administrations) (2) the subjects are adults (3) data for more than one subject was reported. Data from(Bedada and Neerati, 2016;Bedada and Boga, 2017;Bedada and Neerati, 2018;Benowitz et al, 2003;Burckart et al, 1998;Chalasani et al, 2003;Dreisbach et al, 1995;Eap et al, 1998;Girre et al, 1994;He et al, 2019;de la Maza et al, 2000;Liangpunsakul et al, 2005;Lucas et al, 1993;Park et al, 2006;Rajnarayana et al, 2008;Vesell et al, 1995;Wang et al, 2003;Hohmann et al, 2019;Witt et al, 2016).…”

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confidence: 99%

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A physiologically based pharmacokinetic model for CYP2E1 phenotyping via chlorzoxazone

Küttner

Grzegorzewski

Tautenhahn

et al. 2023

Preprint

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The cytochrome P450 (CYP) superfamily of enzymes plays a critical role in the metabolism of drugs, toxins, and endogenous and exogenous compounds. The activity of CYP enzymes can be influenced by a variety of factors, including genetics, diet, age, environmental factors, and disease. Among the major isoforms, CYP2E1 is of particular interest due to its involvement in the metabolism of various low molecular weight chemicals, including alcohols, pharmaceuticals, industrial solvents, and halogenated anesthetics. Metabolic phenotyping of CYPs based on the elimination of test compounds is a useful method for assessing in vivo activity, with chlorzoxazone being the primary probe drug for phenotyping of CYP2E1. The aim of this work was to investigate the effect of changes in CYP2E1 level and activity, ethanol consumption, ethanol abstinence, and liver impairment on the results of metabolic phenotyping with chlorzoxazone. To accomplish this, an extensive pharmacokinetic dataset for chlorzoxazone was established and a physiologically based pharmacokinetic (PBPK) model of chlorzoxazone and its metabolites, 6-hydroxychlorzoxazone and chlorzoxazone-O-glucuronide, was developed and validated. The model incorporates the effect of ethanol consumption on CYP2E1 levels and activity by extending the model with a core ethanol pharmacokinetic model and a CYP2E1 turnover model. The model accurately predicts pharmacokinetic data from several clinical studies and is able to estimate the effect of changes in CYP2E1 levels and activity on chlorzoxazone pharmacokinetics. Regular ethanol consumption induces CYP2E1 over two to three weeks, resulting in increased conversion of chlorzoxazone to 6-hydroxychlorzoxazone and a higher 6-hydroxychlorzoxazone/chlorzoxazone metabolic ratio. After ethanol withdrawal, CYP2E1 levels return to baseline within one week. Importantly, liver impairment has an opposite effect, resulting in reduced liver function via CYP2E1. In alcoholics with liver impairment who also consume ethanol, these factors will have opposite confounding effects on metabolic phenotyping with chlorzoxazone.

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“…CLZ and 6‐OH‐CLZ plasma and urine concentrations were quantified according to a previously published method with changes with regard to the expected therapeutic concentrations. Urine samples (10 μl) were diluted in blank plasma (90 μl) and processed analogue to the pure plasma samples.…”

Section: Methodsmentioning

confidence: 99%

Higher chlorzoxazone clearance in obese children compared with nonobese peers

Gade

Dalhoff

Petersen

et al. 2018

Brit J Clinical Pharma

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Ultrasensitive quantification of the CYP2E1 probe chlorzoxazone and its main metabolite 6-hydroxychlorzoxazone in human plasma using ultra performance liquid chromatography coupled to tandem mass spectrometry after chlorzoxazone microdosing

Cited by 16 publications

References 25 publications

Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome

Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome

A physiologically based pharmacokinetic model for CYP2E1 phenotyping via chlorzoxazone

Higher chlorzoxazone clearance in obese children compared with nonobese peers

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