Zolmitriptan

Zolmitriptan

Clinical data
Trade names	Zomig, others
Other names	BW-311C90; BW311C90; 311C90; BW-311-C-90; ML-004; ML004; [(4S)-2-Oxo-1,3-oxazolidin-4-yl]methyl-N,N-dimethyltryptamine
AHFS/Drugs.com	Monograph
MedlinePlus	a601129
License data	US DailyMed: Zolmitriptan
Pregnancy category	AU: B3
Routes of administration	By mouth, nasal spray
Drug class	Serotonin 5-HT1B and 5-HT1D receptor agonist; Antimigraine agent; Triptan
ATC code	N02CC03 (WHO)
Legal status
Legal status	CA: ℞-only[1] US: ℞-only
Pharmacokinetic data
Bioavailability	Oral: 40%[2]
Protein binding	25%[2]
Metabolism	Liver (CYP1A2-mediated, to active metabolite; also MAOTooltip monoamine oxidase)[2]
Metabolites	• N-Desmethylzolmitriptan[2] • Zolmitriptan N-oxide[2] • Indole acetic acid derivative[2]
Elimination half-life	Zolmitriptan: 3 hours[2] N-Desmethylzolmitriptan: 3.5 hours[2]
Excretion	Urine: ~65%[2] Feces: ~30%[2]
Identifiers
IUPAC name (S)-4-({3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl}methyl)-1,3-oxazolidin-2-one
CAS Number	139264-17-8^Y
PubChem CID	60857
IUPHAR/BPS	60
DrugBank	DB00315^Y
ChemSpider	54844^Y
UNII	2FS66TH3YW
KEGG	D00415^Y
ChEBI	CHEBI:10124^Y
ChEMBL	ChEMBL1185^Y
CompTox Dashboard (EPA)	DTXSID8045933
ECHA InfoCard	100.158.186
Chemical and physical data
Formula	C16H21N3O2
Molar mass	287.363 g·mol^−1
3D model (JSmol)	Interactive image
SMILES O=C1OC[C@@H](N1)Cc2ccc3c(c2)c(c[nH]3)CCN(C)C
InChI InChI=1S/C16H21N3O2/c1-19(2)6-5-12-9-17-15-4-3-11(8-14(12)15)7-13-10-21-16(20)18-13/h3-4,8-9,13,17H,5-7,10H2,1-2H3,(H,18,20)/t13-/m0/s1^Y Key:ULSDMUVEXKOYBU-ZDUSSCGKSA-N^Y
(verify)

Zolmitriptan, sold under the brand name Zomig among others, is a serotonergic medication which is used in the acute treatment of migraine attacks with or without aura and cluster headaches.^[3] It is taken by mouth as a swallowed or disintegrating tablet or as a nasal spray.^[3]

Side effects include neck/throat/jaw pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensations, nausea, heaviness sensation, and dry mouth.^[3] The drug acts as a selective serotonin 5-HT_1B and 5-HT_1D receptor agonist.^[3] Structurally, it is a triptan and a tryptamine derivative.^[3][4]

It was patented in 1990 and was approved for medical use in 1997.^[5][3]

Medical uses

Migraine

Zolmitriptan is used for the acute treatment of migraines with or without aura in adults.^[3] It is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine.^[3]

Off-label uses

• Acute treatment of cluster headaches—Level A recommendation from the American Academy of Neurology^[6]
• Acute treatment of menstrual migraine^[6]

Available forms

Zolmitriptan is available as a swallowed tablet, an orally disintegrating tablet, and as a nasal spray, in doses of 2.5 and 5 mg. People who get migraines from aspartame should not use the disintegrating tablet (Zomig ZMT) as it contains aspartame.^[7]

A 2014 Cochrane review has shown that zolmitriptan 5 mg nasal spray was significantly more effective than the 5 mg oral tablet.^[8]

Contraindications

Zolmitriptan is contraindicated in patients with cerebrovascular or cardiovascular disease because serotonin 5-HT_1B receptors are present in coronary arteries. Such conditions include, but are not limited to, coronary artery disease, stroke, and peripheral vascular disease.^[6] It is also contraindicated in hemiplegic migraine.^[6]

Side effects

Side effects include neck/throat/jaw pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensations, nausea, heaviness sensation, and dry mouth.^[3]

As for cardiovascular side effects, zolmitriptan can increase systolic blood pressure in the elderly and increase diastolic blood pressure in both the elderly and young people. Additionally, there is the side effect of a dose-related increase in sedation. There is a risk for medication withdrawal headache or medication overuse headache.^[6]

Zolmitriptan has a weak affinity for serotonin 5-HT_1A receptors; these receptors have been implicated in the development of serotonin syndrome.^[6]

Interactions

Following administration of cimetidine, the elimination half-life and total exposure of zolmitriptan and its active metabolite were approximately doubled.^[6]

Pharmacology

Mechanism of action

Zolmitriptan is a selective serotonin 5-HT_1B and 5-HT_1D receptor agonist with weak affinity for the serotonin 5-HT_1A receptor.^[9] It also has affinity for other serotonin receptors, including the serotonin 5-HT_1E, 5-HT_1F, 5-HT_2B, 5-HT_5A, and 5-HT₇ receptors.^[9] Conversely, its affinities for the serotonin 5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₄, and 5-HT₆ receptors are negligible or undetectable.^[9]

Its action on serotonin 5-HT_1B and 5-HT_1D receptors causes vasoconstriction in intracranial blood vessels; as well it can inhibit the release of pro-inflammatory neuropeptides from trigeminal perivascular nerve endings. It crosses the blood–brain barrier as evidenced by the presence of radiolabeled zolmitriptan within the cells of the trigeminal nucleus caudalis and nucleus tractus solitarii.^[6]

Pharmacokinetics

Zolmitriptan has a rapid onset of action and has been detected in the brain as early as within 5 minutes of intranasal administration. On average, zolmitriptan has an oral bioavailability of 40%, a mean volume of distribution of 8.3 L/kg after oral administration, and 2.4L/kg after intravenous administration.^[6] According to a study of healthy volunteers, food intake seems to have no significant effect on the effectiveness of zolmitriptan in both men and women.^[10]

Zolmitriptan is a more lipophilic compound with greater central permeability than certain other triptans like sumatriptan.^[11][12] It has been found to cross the blood–brain barrier and enter the central nervous system both in animals and humans.^[13] In a clinical pharmacokinetic study, brain concentrations were about 20% of plasma concentrations.^[14] However, in another clinical study, the drug achieved relatively low occupancy of central serotonin 5-HT_1B receptors (4–5%) as measured by positron emission tomography (PET) imaging.^[13][15][14]

Zolmitriptan is metabolized into three major metabolites by the human hepatic cytochrome P450 enzymes—primarily CYP1A2. Two-thirds of the parent compound breaks down into the active metabolite N-desmethylzolmitriptan (183C91), while the remaining one-third separates into the other two inactive metabolites: zolmitriptan N-oxide and an indole acetic acid derivative. It has an elimination half-life of about 3 hours before it undergoes renal elimination; its clearance is greater than the glomerular filtration rate suggesting that there is some renal tubular secretion of the compound.^[6]

Chemistry

Zolmitriptan is a triptan and a substituted tryptamine.^[3][4] It is specifically the derivative of N,N-dimethyltryptamine (DMT) in which the hydrogen atom at position 5 of the indole ring has been substituted with a [(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl group.^[4]

The experimental log P of zolmitriptan is 1.6 to 1.8.^[4] For comparison, the experimental log P of sumatriptan is 0.93.^[16] It is much more lipophilic than sumatriptan.^[9]

Analogues of zolmitriptan include other triptans like sumatriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan.^[9]

Society and culture

Brand names

Zolmitriptan is marketed by AstraZeneca with the brand names Zomig, Zomigon (Argentina, Canada & Greece), AscoTop (Germany) and Zomigoro (France).

Economics

In 2008, Zomig generated nearly $154 million in sales.^[17]

AstraZeneca's U.S. patent on Zomig tablets expired on November 14, 2012, and its pediatric exclusivity extension expired on May 14, 2013.^[18] The patent in certain European countries has already expired too, and generic drug maker Actavis released a generic version in those countries, starting in March 2012.^[19]

Legal status

In Russia versions of zolmitriptan, which are not registered in the National registry of medications, may be regarded as narcotic drugs (derivatives of dimethyltriptamine).^[20]

Research

Social deficits and aggression

See also: Serenic § Examples, and Empathogen § Mechanism of action

Zolmitriptan, in a modified-release formulation that is being referred to by the developmental code name ML-004 (or ML004), is under development by MapLight Therapeutics for the treatment of pervasive developmental disorders (e.g., autism), agitation, and aggression.^{[21][22][23][24][25][26]} As of June 2023, it is in phase 2 clinical trials for pervasive developmental disorders, phase 1 clinical trials for agitation, and is in the preclinical stage of development for aggression.^[21][22][23]

References

1. "Product monograph brand safety updates". Health Canada. 6 June 2024. Retrieved 8 June 2024.
2. "Zolmitriptan: Uses, Interactions, Mechanism of Action". DrugBank Online. 25 November 1997. Retrieved 27 October 2024.
3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020768s023,021231s014,021450s010lbl.pdf
4. "Zolmitriptan". PubChem. Retrieved 27 October 2024.
5. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 531. ISBN 9783527607495.
6. Abram JA, Patel P (2020). "Zolmitriptan". Statpearls. PMID 32491581. Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
7. Newman LC, Lipton RB (2001). "Migraine MLT-Down: An Unusual Presentation of Migraine in Patients With Aspartame-Triggered Headaches". Headache: The Journal of Head and Face Pain (abstract). 41 (9): 899–901. doi:10.1046/j.1526-4610.2001.01164.x (inactive 9 December 2024). PMID 11703479.
8. Bird S, Derry S, Moore RA (May 2014). "Zolmitriptan for acute migraine attacks in adults". Cochrane Database Syst Rev. 2014 (5): CD008616. doi:10.1002/14651858.CD008616.pub2. PMC 6485805. PMID 24848613.
9. Tfelt-Hansen P, De Vries P, Saxena PR (December 2000). "Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy". Drugs. 60 (6): 1259–1287. doi:10.2165/00003495-200060060-00003. PMID 11152011.
10. Seaber EJ, Peck RW, Smith DA, Allanson J, Hefting NR, van Lier JJ, et al. (November 1998). "The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volunteers". British Journal of Clinical Pharmacology (abstract). 46 (5): 433–439. doi:10.1046/j.1365-2125.1998.00809.x. PMC 1873688. PMID 9833595.
11. Martin GR (October 1997). "Pre-clinical pharmacology of zolmitriptan (Zomig; formerly 311C90), a centrally and peripherally acting 5HT1B/1D agonist for migraine". Cephalalgia. 17 Suppl 18: 4–14. doi:10.1177/0333102497017S1802. PMID 9399012.
12. Lionetto L, Casolla B, Mastropietri F, D'Alonzo L, Negro A, Simmaco M, Martelletti P (August 2012). "Pharmacokinetic evaluation of zolmitriptan for the treatment of migraines". Expert Opin Drug Metab Toxicol. 8 (8): 1043–1050. doi:10.1517/17425255.2012.701618. PMID 22762358.
13. Deen M, Christensen CE, Hougaard A, Hansen HD, Knudsen GM, Ashina M (March 2017). "Serotonergic mechanisms in the migraine brain - a systematic review". Cephalalgia. 37 (3): 251–264. doi:10.1177/0333102416640501. PMID 27013238. The central mechanisms of triptans are a subject of intense debate and have been investigated in several studies. Brain PET studies reported that zolmitriptan crosses the BBB and binds to central 5-HT1B receptors with relatively low occupancy (77,78). It is still unknown whether sumatriptan has a central effect.
14. Wall A, Kågedal M, Bergström M, Jacobsson E, Nilsson D, Antoni G, Frändberg P, Gustavsson SA, Långström B, Yates R (2005). "Distribution of zolmitriptan into the CNS in healthy volunteers: a positron emission tomography study". Drugs R D. 6 (3): 139–147. doi:10.2165/00126839-200506030-00002. PMID 15869317.
15. Varnäs K, Jučaite A, McCarthy DJ, Stenkrona P, Nord M, Halldin C, Farde L, Kanes S (July 2013). "A PET study with [11C]AZ10419369 to determine brain 5-HT1B receptor occupancy of zolmitriptan in healthy male volunteers". Cephalalgia. 33 (10): 853–860. doi:10.1177/0333102413476372. PMID 23430984.
16. "Sumatriptan". PubChem. Retrieved 27 October 2024.
17. "2008 Top 200 generic drugs by retail dollars" (PDF). Archived from the original (PDF) on 2009-05-21.  (332 KB). Drug Topics (May 26, 2009). Retrieved on August 25, 2009.
18. "Generic Zomig-ZMT Availability".
19. "Migraine treatment Zolmitriptan launched by Actavis in Europe". Archived from the original on 2012-03-23.
20. "Постановление Правительства РФ от 30 июня 1998 г. N 681 "Об утверждении перечня наркотических средств, психотропных веществ и их прекурсоров, подлежащих контролю в Российской Федерации" (с изменениями и дополнениями)" (in Russian). Гарант. Retrieved 2019-04-29. ДМТ (диметилтриптамин) и его производные, за исключением производных, включенных в качестве самостоятельных позиций в перечень
21. "ML 004". AdisInsight. 8 June 2023. Retrieved 27 October 2024.
22. "Delving into the Latest Updates on ML-004 with Synapse". Synapse. 28 September 2024. Retrieved 27 October 2024.
23. Hess P (28 April 2023). "Going on Trial: Serotonin drug; psilocybin phase 2; placebo response data". The Transmitter: Neuroscience News and Perspectives. Retrieved 27 October 2024.
24. Wang L, Clark EA, Hanratty L, Koblan KS, Foley A, Dedic N, Bristow LJ (August 2024). "TAAR1 and 5-HT1B receptor agonists attenuate autism-like irritability and aggression in rats prenatally exposed to valproic acid". Pharmacol Biochem Behav. 245: 173862. doi:10.1016/j.pbb.2024.173862. PMID 39197535. Interest in 5-HT1B as a target for ASD is further evidenced by the ongoing Phase 2 clinical trial of ML-004, a modified release form of the 5-HT1B/1D agonist zolmitriptan, which is being evaluated for the treatment of social communication deficits in adolescent and adult subjects with ASD (NCT05081245).
25. "Maplight Autism Study". Cortica. Retrieved 27 October 2024. Purpose: The purpose of this study is to find out whether ML-004, an extended-release version of zolmitriptan, can support with sociability and emotional regulation in adults with ASD.
26. "Zolmitriptan by MapLight therapeutics for Autism Spectrum Disorder (ASD): Likelihood of Approval". Archived from the original on 22 May 2024.

Further reading

• MacGregor EA (1998). "Zolmitriptan clinical studies". Drugs Today. 34 (12): 1027–1033. doi:10.1358/dot.1998.34.12.487488. PMID 14743270.

External links

• "Zolmitriptan Nasal Spray". MedlinePlus.