Mexazolam

Mexazolam

Clinical data
Trade names	Melex, Sedoxil
Other names	13-chloro- 2-(2-chlorophenyl)- 5-methyl- 3-oxa- 6,9-diazatricyclo[8.4.0.02,6] tetradeca- 1(10),11,13-trien- 8-one
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	N05BA25 ( WHO )
Legal status
Legal status	CA: Schedule IV
Pharmacokinetic data
Metabolism	Liver (CYP3A4)
Excretion	Kidney
Identifiers
IUPAC name 10-chloro-11b-(2-chlorophenyl)-3-methyl-2,3,5,7-tetrahydro-[1,3]oxazolo[3,2-d][1,4]benzodiazepin-6-one
CAS Number	31868-18-5
PubChem CID	4177
ChemSpider	4033  Y
UNII	S5969B6237
KEGG	D01316  Y
CompTox Dashboard (EPA)	DTXSID9057715
Chemical and physical data
Formula	C18H16Cl2N2O2
Molar mass	363.24 g·mol−1
3D model (JSmol)	Interactive image
SMILES Clc1ccccc1C42OCC(N2CC(=O)Nc3c4cc(Cl)cc3)C
InChI InChI=1S/C18H16Cl2N2O2/c1-11-10-24-18(13-4-2-3-5-15(13)20)14-8-12(19)6-7-16(14)21-17(23)9-22(11)18/h2-8,11H,9-10H2,1H3,(H,21,23) Y Key:ANUCDXCTICZJRH-UHFFFAOYSA-N Y
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Mexazolam ^[1] (marketed under the trade names Melex and Sedoxil) ^[2] is a drug which is a benzodiazepine derivative. ^[3] Mexazolam has been trialed for anxiety and was found to be effective in alleviating anxiety at one week follow-up. Mexazolam is metabolised via the CYP3A4 pathway. HMG-CoA reductase inhibitors including simvastatin, simvastatin acid, lovastatin, fluvastatin, atorvastatin and cerivastatin inhibit the metabolism of mexazolam, ^[4] but not the HMG-CoA reductase inhibitor pravastatin. ^{[5] [6]} Its principal active metabolites are chlorodesmethyldiazepam (also known as chloronordiazepam or delorazepam, trade name Dadumir) and chloroxazepam (also known as lorazepam, trade name Ativan). ^[7] Researchers have found a dose of 1.67 mg mexazolam equals 5 mg diazepam. ^[8]

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. ^[9] The active metabolites further extend duration of action of the drug. ^{[9] [10]} The elimination half-lives of the active metabolites is 130–200 h, which supports once-daily dosing but also calls for caution regarding accumulation and residual sedative effects during prolonged therapy. ^[9]

Mechanism of action

Mexazolam's primary target is GABA_A receptor, benzodiazepine site, via the active metabolite chloronordiazepam. ^[10] Mexazolam potentiates GABA currents at α2/α3 (anxiolytic) subunit‑containing receptors. The drug has minimal effect on α1 (sedative) amplitude; ^{[11] [10]} as such, mexazolam has lower sedative load compared to classical benzodiazepines ^[10] such as chlordiazepoxide. ^[12]

See also

• Benzodiazepine
• Delorazepam
• Lorazepam

References

1. DE Patent 1954065
2. "Benzodiazepine Names". non-benzodiazepines.org.uk. Archived from the original on 2008-12-08. Retrieved 2009-04-05.
3. Kurono Y, Kamiya K, Kuwayama T, Jinno Y, Yashiro T, Ikeda K (September 1987). "Kinetics and mechanism of the acid-base equilibrium of mexazolam and comparison with those of other commercial benzodiazepinooxazole drugs". Chemical & Pharmaceutical Bulletin. 35 (9): 3831–3837. doi: 10.1248/cpb.35.3831 . PMID   2893667.
4. Mc Donnell CG, Harte S, O'Driscoll J, O'Loughlin C, Van Pelt FN, Shorten GD (September 2003). "The effects of concurrent atorvastatin therapy on the pharmacokinetics of intravenous midazolam". Anaesthesia. 58 (9): 899–904. doi: 10.1046/j.1365-2044.2003.03339.x . PMID   12911366. S2CID   25382546.
5. Ishigami M, Takasaki W, Ikeda T, Komai T, Ito K, Sugiyama Y (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. 30 (8): 904–910. doi:10.1124/dmd.30.8.904. PMID   12124308. S2CID   2620104.
6. Ishigami M, Honda T, Takasaki W, Ikeda T, Komai T, Ito K, et al. (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. 29 (3): 282–288. PMID   11181496.
7. Fernandes H, Moreira R (June 2014). "Mexazolam: clinical efficacy and tolerability in the treatment of anxiety". Neurology and Therapy. 3 (1): 1–14. doi:10.1007/s40120-014-0016-7. PMC   4381915 . PMID   26000220.
8. Inada T, Inagaki A (August 2015). "Psychotropic dose equivalence in Japan". Psychiatry and Clinical Neurosciences. 69 (8): 440–447. doi: 10.1111/pcn.12275 . PMID   25601291.
9. Fernandes H, Moreira R (June 2014). "Mexazolam: clinical efficacy and tolerability in the treatment of anxiety". Neurology and Therapy. 3 (1): 1–14. doi:10.1007/s40120-014-0016-7. PMC   4381915 . PMID   26000220.
10. Fernandes H, Batalha V, Braksator E, Hebeisen S, Bonifácio MJ, Vieira-Coelho MA, et al. (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. 74 (5): 956–968. doi:10.1007/s43440-022-00411-x. PMID   36097257.
11. Soares Da Costa I, Moreira R, Fernandes H (2022). "Tranquilizer/Anxiolytics: Mexazolam". NeuroPsychopharmacotherapy. pp. 2151–2159. doi:10.1007/978-3-030-62059-2_162. ISBN   978-3-030-62058-5.
12. McGrath C, Burrows GD, Norman TR (2000). "The benzodiazepines: A brief review of pharmacology and therapeutics". Anxiolytics. pp. 1–11. doi:10.1007/978-3-0348-8470-9_1. ISBN   978-3-0348-9581-1.