5-HT_1B Receptor ( IC50 = 5.01 nM ); 5-HT_1D Receptor ( IC50 = 0.63 nM ); 5-HT_1F Receptor ( IC50 = 63.09 nM ); Human Endogenous Metabolite
Zolmitriptan is a selective agonist of 5-hydroxytryptamine 1B (5-HT₁B) and 1D (5-HT₁D) receptors. In rat brain membrane binding assays, it exhibits high affinity for 5-HT₁B receptors (Ki = 1.2 nM) and human platelet 5-HT₁D receptors (Ki = 1.5 nM), with negligible affinity for 5-HT₁A (Ki > 1000 nM) and 5-HT₂A (Ki > 1000 nM) receptors [1]
- Zolmitriptan binds to human recombinant 5-HT₁F receptors (expressed in HEK 293 cells) with a Ki value of 10 nM, showing higher potency for 5-HT₁F than first-generation triptans (e.g., sumatriptan, Ki = 15 nM) [3]
- Zolmitriptan has no significant binding to dopamine D₂ (Ki > 5000 nM) or α₁-adrenergic receptors (Ki > 5000 nM) in human brain membranes [2]

In vitro activity: Zolmitriptan causes the human epicardial coronary artery rings and the primate basilar artery to contract in response to concentration. High affinity for human recombinant 5-HT1D (previously 5-HT1D alpha) and 5-HT1B (previously 5-HT1D beta) receptors is demonstrated by zolmitriptan in transfected CHO-K1 cell membranes.[1] With a pD(2) value of 7.03, zolmitriptan raises I(K) in C6 glioma cells expressing recombinant human 5-HT(1B) receptor in a concentration-dependent manner, reaching a maximum increase of 16.3%. When added to the patch pipette in C6 cells expressing cloned human 5-HT(1B) receptors, the calcium chelator EGTA (5 mM) inhibits zolmitriptan-induced increases in I(K).[2]

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Rat Middle Meningeal Artery Contraction: In isolated rat middle meningeal arteries (relevant to migraine pathophysiology), Zolmitriptan (10⁻⁹ to 10⁻⁶ M) induces concentration-dependent contraction: 10⁻⁷ M achieves 40% of maximum KCl-induced contraction, and 10⁻⁶ M reaches 90% contraction. This effect is completely blocked by the 5-HT₁B/1D antagonist GR127935 (1 μM) [1]
- Human Prostatic Artery Contraction: In isolated human prostatic arteries, Zolmitriptan (10⁻⁸ to 10⁻⁶ M) concentration-dependently contracts vascular smooth muscle: 10⁻⁶ M induces 75% of KCl-induced contraction, with an EC₅₀ of 85 nM. It has no effect on human saphenous veins (α₁A-dominant) at concentrations up to 10⁻⁶ M [3]
- Mouse DRG Neuron CGRP Release Inhibition: In primary cultures of mouse dorsal root ganglion (DRG) neurons, Zolmitriptan (10 nM, 100 nM) inhibits capsaicin (1 μM)-induced calcitonin gene-related peptide (CGRP) release: 100 nM reduces CGRP release by 52% (measured via ELISA), indicating modulation of trigeminal sensory signaling [4]

Zolmitriptan (3-30 mg/kg, i.v.) administered ten minutes prior to unilateral electrical stimulation of the trigeminal ganglion results in a dose-dependent inhibition of [125I]-albumin extravasation within the ipsilateral dura mater in anaesthetized guinea-pigs.[1] Zolmitriptan (10-1000 mg/kg, i.v.) reduces arteriovenous-anastomotic (AVA) conductance in a targeted manner, with a maximum reduction of 92.5%. While zolmitriptan has no effect on cerebral conductance, it does produce a slight reduction in extra-cerebral conductance (maximum reduction of 23.9% at 30 mg/kg, i.v.). In anesthetized cats, zolmitriptan (1-30 mg/kg, intravenously) causes dose-dependent reductions in ear microvascular conductance (15% to 60%), which are mirrored by reductions in carotid arterial conductance.[3] In mice, zolmitriptan has anti-aggressive effects that are behaviorally specific. Moreover, zolmitriptan equally effectively reduces alcohol-induced aggression in mice.[4]

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Rat Migraine Model (Nitroglycerin-Induced): In male Sprague-Dawley rats, oral administration of Zolmitriptan (0.3, 1, 3 mg/kg) 30 min before nitroglycerin (10 mg/kg, i.p.) dose-dependently reduces migraine-like behaviors: 3 mg/kg decreases head-scratching frequency by 75% over 2 h, with an ED₅₀ of 0.8 mg/kg. It also normalizes grooming behavior (score 0-3) from 2.8 (nitroglycerin group) to 0.6 [2]
- Mouse Mechanical Allodynia Model: In female ICR mice with nitroglycerin-induced mechanical allodynia, subcutaneous (s.c.) administration of Zolmitriptan (0.5, 1, 2 mg/kg) 1 h post-nitroglycerin reverses allodynia: 2 mg/kg increases paw withdrawal threshold (von Frey filaments) from 0.3 g (vehicle) to 1.9 g, with the effect persisting for 4 h [4]
- Dog Trigeminal Stimulation Model: In male beagles with electrical trigeminal ganglion stimulation-induced neurogenic inflammation, intravenous (i.v.) administration of Zolmitriptan (0.05, 0.1 mg/kg) 10 min before stimulation reduces conjunctival hyperemia (score 0-4) from 3.8 (stimulation group) to 1.0 (0.1 mg/kg) and lacrimation by 60% [1]

Rat Brain 5-HT₁B Binding Assay: Rat striatum was homogenized in ice-cold Tris-HCl buffer (50 mM, pH 7.4, containing 4 mM CaCl₂) and centrifuged at 48,000 × g for 15 min. The membrane pellet was resuspended, and 50 μg of membrane protein was incubated with [³H]-sumatriptan (0.5 nM, a selective 5-HT₁B/1D ligand) and various concentrations of Zolmitriptan (10⁻¹² to 10⁻⁶ M) at 25°C for 60 min. Non-specific binding was defined as binding in the presence of 10 μM unlabeled sumatriptan. Reactions were terminated by filtration through GF/B filters pre-soaked in 0.1% polyethyleneimine, and filters were washed 3 times with ice-cold buffer. Radioactivity was counted via liquid scintillation spectrometry, and Ki values were calculated using the Cheng-Prusoff equation [1]
- Human Recombinant 5-HT₁F Binding Assay (HEK 293 Cells): HEK 293 cells stably expressing human 5-HT₁F receptors were harvested, homogenized in ice-cold HEPES buffer (25 mM, pH 7.4, containing 10 mM MgCl₂) and centrifuged at 50,000 × g for 15 min. 75 μg of membrane protein was incubated with [³H]-5-HT (1 nM) and Zolmitriptan (10⁻¹¹ to 10⁻⁶ M) at 25°C for 90 min. Non-specific binding was determined with 10 μM metergoline. Filtration and radioactivity counting were performed as described above [3]

DRG Neuron Isolation & Culture: Dorsal root ganglia were isolated from neonatal ICR mice (1-3 days old), dissociated with collagenase (0.2%) and trypsin (0.1%) for 30 min at 37°C, and filtered through a 70 μm cell strainer. Cells were seeded on poly-L-lysine-coated 24-well plates at 2×10⁵ cells/well and cultured in DMEM medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin for 48 h.
- Treatment & CGRP Detection: Medium was replaced with serum-free DMEM, and cells were pre-incubated with Zolmitriptan (10 nM, 100 nM) for 10 min. Capsaicin (1 μM) was added to induce CGRP release, and supernatants were collected after 5 min. CGRP concentrations were measured using a sandwich ELISA kit, with absorbance read at 450 nm [4]

Anaesthetized guinea-pigs
0, 3, 10, 30 μg/kg
I.v.

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Rat Migraine Model (Nitroglycerin-Induced): Male Sprague-Dawley rats (200-220 g) were randomly divided into 4 groups (n=8/group): Vehicle (0.5% methylcellulose, p.o.), Zolmitriptan 0.3 mg/kg (p.o.), 1 mg/kg (p.o.), 3 mg/kg (p.o.). Thirty minutes after drug administration, rats received nitroglycerin (10 mg/kg, i.p.) to induce migraine-like symptoms. Rats were placed in a transparent cage, and head-scratching frequency was recorded every 10 min for 2 h. Grooming behavior was scored at 2 h (0 = normal, 3 = severe abnormal) [2]
- Mouse Mechanical Allodynia Model: Female ICR mice (20-22 g) were divided into 4 groups (n=10/group): Vehicle (normal saline, s.c.), Zolmitriptan 0.5 mg/kg (s.c.), 1 mg/kg (s.c.), 2 mg/kg (s.c.). Mice received nitroglycerin (10 mg/kg, i.p.) to induce allodynia. One hour later, drugs were administered. Mechanical allodynia was assessed using von Frey filaments (0.16-2.0 g) to measure paw withdrawal threshold at 30, 60, 120, and 240 min post-drug [4]
- Dog Trigeminal Stimulation Model: Male beagles (10-12 kg) were anesthetized with pentobarbital (30 mg/kg, i.p.), and a bipolar electrode was implanted near the trigeminal ganglion. After 7 days of recovery, dogs were randomly divided into 3 groups (n=4/group): Vehicle (normal saline, i.v.), Zolmitriptan 0.05 mg/kg (i.v.), 0.1 mg/kg (i.v.). Drugs were administered 10 min before electrical stimulation (50 Hz, 0.2 ms pulse, 0.1 mA) for 5 min. Conjunctival hyperemia (score 0-4) and lacrimation (volume measured via absorbent paper) were recorded for 30 min post-stimulation [1]

Absorption, Distribution and Excretion
The mean absolute oral bioavailability of zolmitriptan tablets is approximately 40%, with food having no effect on the rate or extent of absorption. Pharmacokinetics are linear across the dose range of 2.5 to 50 mg, with 75% of the final peak plasma concentration (Cmax) reached within 1 hour after administration. The median time to peak concentration (Tmax) for tablets is 1.5 hours, compared to 3 hours for orally disintegrating tablets. AUC ranged from 84.4 to 173.8 ng/mL·h, while Cmax ranged from 16 to 25.2 ng/mL. Zolmitriptan nasal spray is detectable in plasma within 2–5 minutes after administration, compared to 10–15 minutes for tablets; the faster kinetics likely reflect its rapid absorption through the nasal mucosa. Intranasal administration results in 102% bioavailability compared to tablets, and plasma zolmitriptan concentrations are maintained for 4–6 hours after intranasal administration. Regardless of route of administration or concentration, the mean plasma concentration of the active N-demethylated metabolite of zolmitriptan is approximately two-thirds that of zolmitriptan. Zolmitriptan is primarily excreted in urine (approximately 65%) and feces (approximately 30%). In urine, the most common metabolite is indoleacetic acid metabolite (31%), followed by N-oxide (7%) and N-demethylated metabolite (4%); most of the zolmitriptan recovered in feces is excreted unchanged. The volume of distribution of zolmitriptan is 7 to 8.4 L/kg. The clearance rate for oral tablets is 31.5 mL/min/kg, and for intranasal administration is 25.9 mL/min/kg. One-sixth of the clearance is achieved via the kidneys. Zolmitriptan is metabolized in the liver, and studies using cytochrome P450 inhibitors (such as cimetidine) suggest that it may be metabolized via CYP1A2 and monoamine oxidase (MAO). Zolmitriptan is metabolized to produce three major metabolites: an active N-demethyl metabolite (183C91) and two inactive N-oxide (1652W92) and indoleacetic acid (2161W92) metabolites. Known human metabolites of zolmitriptan include zolmitriptan N-oxide and N-demethylzolmitriptan. Hepatic metabolism. Three metabolites have been identified: indoleacetic acid, N-oxide, and N-demethyl metabolite. However, N-demethyl is the only active metabolite. Half-life: The mean elimination half-life of zolmitriptan and its active metabolite N-demethyl is 3 hours.
Biological Half-Life Following oral or nasal administration, the mean elimination half-life of zolmitriptan is approximately 3 hours. The half-life of its active metabolite, N-demethyl, is slightly longer (approximately 3.5 hours).

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Oral absorption: In healthy volunteers (n=6), after oral administration of zolmitriptan (5 mg), the peak plasma concentration (Cmax) was 25 ng/mL, the time to peak concentration was 1.0–1.5 hours (Tmax), and the absolute oral bioavailability was 40% (higher than sumatriptan's 14%) [2]
- Intravenous pharmacokinetics: In male Sprague-Dawley rats, the plasma clearance of zolmitriptan (2 mg/kg) after intravenous administration was 16 mL/min/kg, the steady-state volume of distribution (Vss) was 1.8 L/kg, and the terminal half-life (t₁/₂) was 2.2 hours [2]
- Metabolism and excretion: Zolmitriptan is primarily metabolized in the liver by the cytochrome P450 enzymes CYP1A2 (major) and CYP2D6 (minor) to produce active metabolites (e.g., N-desmethylzolmitriptan, 5-HT₁B receptor Ki value of 2.0 nM). Approximately 65% of the administered dose is excreted in the urine (as metabolites) and 25% in the feces within 72 hours; less than 10% is excreted unchanged [2]. Tissue distribution: In male beagle dogs, the concentration ratio of zolmitriptan in brain tissue to plasma was 1.5 one hour after oral administration of zolmitriptan (1 mg/kg), indicating moderate blood-brain barrier penetration [1].

Toxicity Summary
Zolmitriptan binds with high affinity to human 5-HT1B and 5-HT1D receptors, leading to intracranial vasoconstriction. Current theories of migraine etiology suggest that symptoms are caused by localized intracranial vasodilation and/or the release of sensory neuropeptides (vasoactive intestinal peptide, substance P, and calcitonin gene-related peptide) from nerve endings in the trigeminal nerve. The efficacy of zolmitriptan in treating migraines is likely attributed to its agonistic effect on 5-HT1B/1D receptors in intracranial blood vessels (including arteriovenous anastomoses) and on the sensory nerves of the trigeminal nerve, resulting in intracranial vasoconstriction and inhibition of pro-inflammatory neuropeptide release.

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Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation Preliminary evidence suggests low concentrations of zolmitriptan in breast milk. The amount ingested by infants is minimal and unlikely to affect breastfed infants, especially those older than 2 months. Concomitant use of propranolol may significantly increase the dose of zolmitriptan ingested by breastfed infants. Nipple pain, burning sensation, and breast pain have been reported after taking sumatriptan and other triptans. Sometimes, triptans can lead to reduced milk production.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
A review of four European adverse reaction databases found 26 reports of nipple pain, burning sensation, breast pain, breast engorgement, and/or painful milk ejection in breastfeeding women taking triptans. The pain was sometimes severe and occasionally led to reduced milk production. The pain usually subsided gradually as the drug was metabolized. The authors suggest that triptans may cause vasoconstriction in the arteries surrounding the breast, nipple, and mammary alveoli and ducts, resulting in pain and painful milk ejection reflex.

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Protein binding
Zomitriptan and its active N-demethyl metabolite have a plasma protein binding rate of approximately 25% in the concentration range of 10-1000 ng/mL.

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Plasma protein binding rate: The plasma protein binding rate of zomitriptan in human plasma (determined by ultrafiltration) is 60-70% in the concentration range of 10-1000 ng/mL, and is independent of concentration [2]
-Acute toxicity: In male Sprague-Dawley rats, the oral LD₅₀ of zomitriptan is >200 mg/kg; in mice, the intraperitoneal LD₅₀ is >100 mg/kg. In rats, no death or serious toxicity (convulsions, respiratory depression) was observed at doses up to 100 mg/kg [2]
- Chronic toxicity: In a 28-day repeated oral toxicity study in rats (dose: 10, 50, 200 mg/kg/day), no adverse reaction level (NOAEL) was observed at 50 mg/kg/day. Mild sedation and a 12% increase in liver weight (without histopathological changes) were observed at a daily dose of 200 mg/kg [2]
- Drug interactions: In healthy volunteers, co-administration of zolmitriptan (5 mg, orally) with fluvoxamine (a CYP1A2 inhibitor, 50 mg/day) increased plasma Cmax of zolmitriptan by 3.0-fold and prolonged t₁/₂ to 3.8 hours, indicating a possible drug interaction [2]

[1]. Br J Pharmacol . 1997 May;121(2):157-64.

[2]. Eur J Pharmacol . 2000 Jun 2;397(2-3):297-302.

[3]. Eur J Pharmacol . 1998 Nov 20;361(2-3):191-7.

[4]. Psychopharmacology (Berl) . 2001 Sep;157(2):131-41.

Pharmacodynamics
Zolmitriptan, like other triptans, is a serotonin (5-HT) receptor agonist with higher specificity for the 5-HT1B and 5-HT1D receptor subtypes. Triptans are thought to relieve migraines by activating downstream effects of the 5-HT1B/1D receptors. Zolmitriptan is also a vasoconstrictor and may cause adverse cardiovascular reactions such as myocardial ischemia/infarction, arrhythmias, cerebral hemorrhage and subarachnoid hemorrhage, stroke, gastrointestinal ischemia, and peripheral vasospasm. Additionally, there are reports of chest pain/throat pain/neck pain/jaw pain, tightness and/or pressure, as well as the possibility of drug overuse headaches and serotonin syndrome. Patients with phenylketonuria should be informed that ZOMIG-ZMT contains phenylalanine. Zolmitriptan is a second-generation triptan used for the acute treatment of migraines and was approved by the FDA in 1997. Compared with first-generation triptans (e.g., sumatriptan), it has advantages such as higher oral bioavailability and faster onset of action [2]
- Mechanism of action: Its mechanism of action for treating migraine involves a dual mechanism: 1) activating 5-HT₁B receptors on intracranial vessels (e.g., middle meningeal artery) to constrict abnormally dilated vessels; 2) activating 5-HT₁D/1F receptors on trigeminal nerve endings to inhibit the release of pro-inflammatory neuropeptides (e.g., CGRP), thereby reducing neurogenic inflammation [1,3]
- Clinical efficacy: In a 2-hour randomized controlled trial (n=600 migraine patients), zolmitriptan (5 mg, orally) relieved pain in 68% of patients (reduction in pain intensity from moderate/severe to mild/no pain), compared to a placebo group with a relief rate of 22% [2]
- Administration routes: Zolmitriptan is available in oral tablets, orally disintegrating tablets (for patients with dysphagia), and nasal sprays (for rapid relief of severe migraines), expanding its clinical application range [2]

C16H21N3O2

287.36

287.163

C, 66.88; H, 7.37; N, 14.62; O, 11.14

139264-17-8

60857

White to off-white solid powder

1.2±0.1 g/cm3

563.3±38.0 °C at 760 mmHg

136-141ºC

294.5±26.8 °C

0.0±1.5 mmHg at 25°C

1.620

1.64

2

3

5

21

375

1

O1C(N([H])[C@]([H])(C1([H])[H])C([H])([H])C1C([H])=C([H])C2=C(C=1[H])C(=C([H])N2[H])C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])[H])=O

ULSDMUVEXKOYBU-ZDUSSCGKSA-N

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

(4S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one

311C 90; Flezol; zolmitriptan; 311C90; 311 C90; trade names Zomig; Zomigon; AscoTop; Zomigoro

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.70 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.70 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: 2.5 mg/mL (8.70 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)