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 (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]

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

Absorption, Distribution and Excretion
Zolmitriptan tablets have a mean absolute oral bioavailability of approximately 40%, with food having no effect on the rate or extent of absorption. The dosing kinetics are linear over a range of 2.5 to 50 mg with 75% of the eventual Cmax being attained within 1 hour of dosing. The median Tmax for the tablet form is 1.5 hours, while for the orally disintegrating tablet form, it is 3 hours. The AUC across studies was in the range of 84.4-173.8 ng/mL*h while the Cmax was between 16 and 25.2 ng/mL. Zolmitriptan administered as a nasal spray is detected in the plasma within 2-5 minutes, compared to 10-15 minutes for the tablet form; the faster kinetics likely reflect fast absorption across the nasal mucosa. The bioavailability compared to the tablet is 102%, and plasma zolmitriptan concentration is maintained for 4-6 hours after intranasal delivery. The active N-desmethyl metabolite of zolmitriptan has a mean plasma concentration that is roughly two-thirds of zolmitriptan, regardless of dosage route or concentration.
Zolmitriptan is primarily excreted in urine (approximately 65%) and feces (approximately 30%). Within urine, the most common form is the indole acetic acid metabolite (31%), followed by the N-oxide (7%), and N-desmethyl (4%) metabolites; the majority of zolmitriptan recovered in feces remains unchanged.
Zolmitriptan has a volume of distribution between 7 and 8.4 L/kg.
Zolmitriptan has a clearance of 31.5 mL/min/kg for oral tablets and 25.9 mL/min/kg for nasal administration; one-sixth of the clearance is renal.

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Metabolism / Metabolites
Zolmitriptan is metabolized in the liver, and studies using cytochrome P450 inhibitors like [cimetidine] suggest that it is likely metabolized by CYP1A2, as well as by monoamine oxidase (MAO). Zolmitriptan metabolism results in three major metabolites: an active N-desmethyl metabolite (183C91) as well as inactive N-oxide (1652W92) and indole acetic acid (2161W92) metabolites.
Zolmitriptan has known human metabolites that include Zolmitriptan N-oxide and N-Desmethylzolmitriptan.
Hepatic. There have been three metabolites identified: indole acetic acid, N -oxide, and N-desmethyl metabolites. However, the N-desmethyl is the only active metabolite.
Half Life: The mean elimination half-life of zolmitriptan and of the active N-desmethyl metabolite is 3 hours.

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Biological Half-Life
Zolmitriptan has a mean elimination half-life of approximately three hours following oral or nasal administration. Its active N-desmethyl metabolite has a slightly longer (approximately 3.5 hours) half-life.

Toxicity Summary
Zolmitriptan binds with high affinity to human 5-HT_1B and 5-HT_1D receptors leading to cranial blood vessel constriction. Current theories proposed to explain the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of zolmitriptan for the treatment of migraine headache can most likely be attributed to the agonist effects at the 5HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Preliminary evidence indicates that zolmitriptan levels in breastmilk are low. Amounts ingested by the infant are small and unlikely to affect the nursing infant, especially if the infant is older than 2 months. Concurrent use of propranolol might increase the zolmitriptan dose received by the breastfed infant substantially. Painful, burning nipples and breast pain have been reported after doses of sumatriptan and other triptans. This has occasionally been accompanied by a decrease in milk production.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
A review of four European adverse reaction databases found 26 reported cases of, painful, burning nipples, painful breasts, breast engorgement and/or painful milk ejection in women who took a triptan while nursing. Pain was sometimes intense and occasionally led to decreased milk production. Pain generally subsided with time as the drug was eliminated. The authors proposed that triptans may cause vasoconstriction of the arteries in the breast, nipples, and the arteries surrounding the alveoli and milk ducts, causing a painful sensation and a painful milk ejection reflex.

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Protein Binding
Zolmitriptan and its active N-desmethyl metabolite remain approximately 25% bound to plasma proteins over a concentration range of 10-1000 ng/mL.

[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-hydroxytryptamine; 5-HT) receptor agonist, with enhanced specificity for the 5-HT_1B and 5-HT_1D receptor subtypes. It is through the downstream effects of 5-HT_1B/1D activation that triptans are proposed to provide acute relief of migraines. Zolmitriptan is also a vasoconstrictor, leading to possible adverse cardiovascular effects such as myocardial ischemia/infarction, arrhythmias, cerebral and subarachnoid hemorrhage, stroke, gastrointestinal ischemia, and peripheral vasospastic reactions. In addition, chest/throat/neck/jaw pain, tightness, and/or pressure has been reported, along with the possibility of medication overuse headaches and serotonin syndrome. Patients with phenylketonuria should be advised that ZOMIG-ZMT contains phenylalanine.

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.)