Chemistry:Metaxalone

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Metaxalone, sold under the brand name Skelaxin, is a muscle relaxant medication used to relax muscles and relieve pain caused by strains, sprains, and other musculoskeletal conditions.[1] It is a moderately strong muscle relaxant, with relatively low incidence of side effects.[2][3][4] Its exact mechanism of action is not known, but it may be due to general central nervous system depression.[1] Studies in vitro have shown metaxalone to suppress production of pro-inflammatory cytokines such as TNF-α and IL-6 and increase production of the antiinflammatory cytokine IL-13,[5][6] however it also inhibits MAO-A and this may both contribute to its therapeutic effects and also is linked to toxicity in overdose.[7][8]

Common side effects include nausea, vomiting, drowsiness, and central nervous system (CNS) side effects, such as dizziness, headache, and irritability.[1]

The metabolism of metaxalone involves enzymes CYP1A2 and CYP2C19 in the cytochrome P450 system. Because many medications are metabolized by enzymes in this system, precaution must be taken when administering it with other medications involving the P450 system to avoid interactions.[9]

Because of the potential for side effects, this drug is considered high risk in the elderly.

Pharmacokinetics

Metaxalone exhibits increased bioavailability when taken with food.[10] Specifically, in one study, compared to fasted conditions, the presence of food at the time of drug administration increased Cmax by 77.5%, AUC0-t by 23.5%, and AUC0-∞ by 15.4%.[11] Metaxalone is a substrate of CYP1A2 and CYP2C19, an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A, and an inducer of CYP1A2 and CYP3A4.[9]

Assay

Nirogi et al.[11] reported a liquid chromatographic method coupled to tandem mass spectrometry for the quantification of metaxalone in human plasma. A stability-indicating HPLC method was introduced by P. K. Sahu et al.[12] Metaxalone has been used as an internal standard for few analytical methods.[13][14]

References

  1. ↑ 1.0 1.1 1.2 "Skelaxin- metaxalone tablet". DailyMed. U.S. National Library of Medicine. 27 April 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7a4163f2-c553-4d14-7e98-d14c5c7f772a. 
  2. ↑ "Centrally acting oral skeletal muscle relaxants". American Journal of Hospital Pharmacy 37 (10): 1313–1323. October 1980. PMID 6999895. 
  3. ↑ "A review of three commonly prescribed skeletal muscle relaxants". Journal of Back and Musculoskeletal Rehabilitation 15 (2): 63–66. January 2000. doi:10.3233/bmr-2000-152-303. PMID 22388444. 
  4. ↑ "Commonly used muscle relaxant therapies for acute low back pain: a review of carisoprodol, cyclobenzaprine hydrochloride, and metaxalone". Clinical Therapeutics 26 (9): 1355–1367. September 2004. doi:10.1016/j.clinthera.2004.09.008. PMID 15530999. 
  5. ↑ "Metaxalone Suppresses Production of Inflammatory Cytokines Associated with Painful Conditions in Mouse Macrophages RAW264.7 Cells in Vitro: Synergistic Effect with β-caryophyllene". Current Molecular Medicine 20 (8): 643–652. 2020. doi:10.2174/1566524020666200217102508. PMID 32065089. 
  6. ↑ "MAO-A Inhibition by Metaxalone Reverts IL-1β-Induced Inflammatory Phenotype in Microglial Cells". International Journal of Molecular Sciences 22 (16): 8425. August 2021. doi:10.3390/ijms22168425. PMID 34445126. 
  7. ↑ "Serotonin syndrome following metaxalone overdose and therapeutic use of a selective serotonin reuptake inhibitor". Clinical Toxicology (Philadelphia, Pa.) 53 (3): 185–187. March 2015. doi:10.3109/15563650.2015.1009993. PMID 25671244. 
  8. ↑ "Monoamine oxidase A inhibition by toxic concentrations of metaxalone". Clinical Toxicology (Philadelphia, Pa.) 58 (5): 383–387. May 2020. doi:10.1080/15563650.2019.1648815. PMID 31373522. 
  9. ↑ 9.0 9.1 Du J, Roberts RH, "Metaxalone products, method of manufacture, and method of use", US patent 7378434, published 2008-05-27, issued 27 May 2008, assigned to Takeda Pharmaceuticals USA Inc.and Mutual Pharmaceutical Company, Inc.
  10. ↑ "Skelaxin Package Insert". King Pharmaceuticals, Inc.. http://www.kingpharm.com/products/product_document.cfm?brand_name=Skelaxin&product_specific_name=&document_type_code=PI. 
  11. ↑ 11.0 11.1 "Quantification of metaxalone in human plasma by liquid chromatography coupled to tandem mass spectrometry". Journal of Analytical Toxicology 30 (4): 245–251. May 2006. doi:10.1093/jat/30.4.245. PMID 16803662. 
  12. ↑ "Development and Validation of Stability Indicating RP-HPLC Method for the Determination of Metaxalone in Bulk and its Pharmaceutical Formulations". Journal of Chemistry 8 (s1): S439–S447. 2011. doi:10.1155/2011/645710. 
  13. ↑ "High throughput LC-MS/MS method for simultaneous quantification of lamivudine, stavudine and nevirapine in human plasma". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 853 (1–2): 320–332. June 2007. doi:10.1016/j.jchromb.2007.03.047. PMID 17481969. 
  14. ↑ "HPLC-ESI-MS/MS validated method for simultaneous quantification of zopiclone and its metabolites, N-desmethyl zopiclone and zopiclone-N-oxide in human plasma". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 864 (1–2): 137–148. March 2008. doi:10.1016/j.jchromb.2008.02.004. PMID 18313371. 



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