Mexazolam

Pharmacokinetics

Mexazolam is a long-acting benzodiazepine that undergoes extensive hepatic metabolism. In humans, the parent drug is primarily oxidized by cytochrome P450 3A isoforms, yielding two active benzodiazepine metabolites: chloronordiazepam and chloroxazepam. Mexazolam follows biphasic elimination profile: the initial distribution phase has a half-life of approximately 1.4 hours, reflecting rapid tissue uptake and first-pass metabolism, following by a terminal phase with a half-life of about 76 hours. The long duration of the terminal phase driven by high plasma protein binding (over 90 percent) and gradual release from peripheral compartments. The active metabolites further extend duration of action of the drug. The elimination half-lives of the active metabolites is , which supports once-daily dosing but also calls for caution regarding accumulation and residual sedative effects during prolonged therapy.

Mechanism of action

Mexazolam's primary target is GABAA receptor, benzodiazepine site, via the active metabolite chloronordiazepam. Mexazolam potentiates GABA currents at α2/α3 (anxiolytic) subunit‑containing receptors. The drug has minimal effect on α1 (sedative) amplitude; as such, mexazolam has lower sedative load compared to classical benzodiazepines such as chlordiazepoxide.

References

References

1. DE Patent 1954065
2. "Benzodiazepine Names". non-benzodiazepines.org.uk.
3. (September 1987). "Kinetics and mechanism of the acid-base equilibrium of mexazolam and comparison with those of other commercial benzodiazepinooxazole drugs". Chemical & Pharmaceutical Bulletin.
4. (September 2003). "The effects of concurrent atorvastatin therapy on the pharmacokinetics of intravenous midazolam". Anaesthesia.
5. (August 2002). "Sex difference in inhibition of in vitro mexazolam metabolism by various 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors in rat liver microsomes". Drug Metabolism and Disposition.
6. (March 2001). "A comparison of the effects of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) reductase inhibitors on the CYP3A4-dependent oxidation of mexazolam in vitro". Drug Metabolism and Disposition.
7. (June 2014). "Mexazolam: clinical efficacy and tolerability in the treatment of anxiety". Neurology and Therapy.
8. (August 2015). "Psychotropic dose equivalence in Japan". Psychiatry and Clinical Neurosciences.
9. "Mexazolam and Alprazolam in the Treatment of Generalised Anxiety Disorder: A Double-Blind, Randomised Clinical Trial". Clin Drug Invest..
10. (June 2014). "Mexazolam: clinical efficacy and tolerability in the treatment of anxiety". Neurology and Therapy.
11. (2022). "NeuroPsychopharmacotherapy".
12. (October 2022). "Voltage-clamp evidence of GABA_A receptor subunit-specific effects: pharmacodynamic fingerprint of chlornordiazepam, the major active metabolite of mexazolam, as compared to alprazolam, bromazepam, and zolpidem". Pharmacological Reports.
13. (2000). "Anxiolytics".