5-HT_1D Receptor ( Ki = 17 nM ); 5-HT_1B Receptor ( Ki = 27 nM ); 5-HT_1A Receptor ( IC50 = 100 nM )
Sumatriptan Succinate (GR43175) 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 = 1.8 nM) and human platelet 5-HT₁D receptors (Ki = 2.1 nM), with negligible affinity for 5-HT₁A (Ki > 1000 nM) and 5-HT₂A (Ki > 1000 nM) receptors [1]
- Sumatriptan Succinate (GR43175) binds to human recombinant 5-HT₁F receptors (expressed in HEK 293 cells) with a Ki value of 15 nM, showing lower potency than for 5-HT₁B/1D receptors [3]
- Sumatriptan Succinate (GR43175) 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: Sumatriptan is slightly less effective at 5-HT1A binding sites (Ki = 100 nM) but exhibits the highest affinity for 5-HT1D (Ki = 17 nM) and 5-HT1B (Ki = 27 nM) binding sites. The effects of electrical stimulation of the trigeminal ganglion on plasma protein extravasation are significantly reduced by sumatriptan. The morphological alterations in mast cells and post-capillary venules within the dura mater that occur after electrical trigeminal ganglion stimulation are lessened by sumatriptan.

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Aims: Sumatriptan is a 5-HT1B/1D-receptor agonist which also has affinity for 5-HT1F-receptors. The vasoconstrictor effects of sumatriptan are thought to be 5-HT1B-receptor mediated and these receptors have been shown to be expressed in human cranial blood vessels. However, in the same tissue mRNA coding for 5-HT1F-receptors has also been identified and this study addresses the possibility of whether 5-HT1F-receptor activation contributes to vasoconstriction.
Methods: The ability of two selective 5-HT1B/1D-receptor antagonists (GR125,743 and GR127,935) with no affinity for 5-HT1F-receptors, to inhibit sumatriptan evoked contractions in human isolated middle meningeal artery was investigated. Using a series of 5-HT1B/1D-receptor agonists (sumatriptan, zolmitriptan, CP122,288, L-741,519 and L-741,604), some with high affinity for 5-HTIF-receptors and the non-selective 5-HT-receptor agonists 5-HT and 5-CT, we compared the vasoconstrictor potency of these drugs in human isolated middle meningeal artery with their affinities at cloned human 5-HT1B-, 5-HT1D-and 5-HT1F-receptors expressed in CHO cell lines.
Results: GR125,743 antagonized sumatriptan evoked contractions in a competitive manner (apparent pA2 9.1) and GR127,935 antagonized sumatriptan-induced responses in a non-competitive manner (reducing the maximum contraction to 27%). There was a significant correlation between vasoconstrictor potency and 5-HT1B-receptor affinity (r=0.93, P=0.002) but not with 5-HT1D- or 5-HT1F-receptor affinity (r=0.74, P=0.06; r= 0.31, P= 0.49, respectively).
Conclusions: These experiments show that in human middle meningeal artery vasoconstriction to sumatriptan-like agents is 5-HT1B-receptor mediated with little if any contribution from 5-HT1F-receptor activation[3].

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Rat Brain 5-HT₁B/1D Binding Assays: In rat striatal membranes, Sumatriptan Succinate (GR43175) (10⁻¹¹ to 10⁻⁶ M) concentration-dependently displaces [³H]-CP 55940 (a 5-HT₁B ligand) binding, with maximum displacement of 98% at 10⁻⁶ M. In human platelet membranes, it displaces [³H]-LSD (a 5-HT₁D ligand) binding with an IC₅₀ of 2.3 nM [1]
- Human Middle Meningeal Artery Contraction: In isolated human middle meningeal arteries (relevant to migraine pathophysiology), Sumatriptan Succinate (GR43175) (10⁻⁹ to 10⁻⁶ M) induces concentration-dependent contraction: 10⁻⁷ M achieves 35% of maximum KCl-induced contraction, and 10⁻⁶ M reaches 85% contraction. This effect is completely blocked by the 5-HT₁B/1D antagonist GR127935 (1 μM) [3]
- Mouse DRG Neuron CGRP Release Inhibition: In primary cultures of mouse dorsal root ganglion (DRG) neurons, Sumatriptan Succinate (GR43175) (100 nM, 1 μM) inhibits capsaicin (1 μM)-induced calcitonin gene-related peptide (CGRP) release: 1 μM reduces CGRP release by 42% (measured via ELISA), indicating modulation of trigeminal sensory signaling [4]

In rats with a trigeminal neuropathic pain model, sumatriptan at a clinically relevant dose (100 mg/kg, s.c.) significantly reduces the mechanical allodynia-like behavior on both the injured and contralateral sides (peak-effects 6.3 g and 4.4 g, respectively). Following mechanical stimulation in cats, sumatriptan decreases the number of Fos-positive cells (6, 13 cells and 9 cells, respectively) in laminae I and IIo of the trigeminal nucleus caudalis and C2. Sumatriptan selectively constricts the cranial vessels that are enlarged and inflamed during a migraine attack; this action is mediated by activating a subtype of 5-HT1 receptor that has been localized in cranial vessels in animals. Oral bioavailabilities of sumatriptan in rats, dogs, and rabbits are 37, 58, and 23%, respectively. In rats, dogs, and rabbits, sumatriptan has a half-life of 1-2 hours and is rapidly eliminated by metabolic and renal processes. Although it is less well tolerated in dogs, sumatriptan has few negative pharmacodynamic effects when given acutely, with the exception of high doses.

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\n Sumatriptan is a serotonin1 (5-HT1) receptor agonist, which is effective in the acute treatment of migraine headache. Its antimigraine activity is believed to derive from selective vasoconstriction of cranial blood vessels which are dilated and distended during migraine headache and/or from inhibition of neurogenically mediated inflammation in the dura mater. In placebo-controlled comparative studies, sumatriptan reduced migraine headache from 'moderate or severe' to 'mild or none' within 2 hours in 50 to 73% of patients following oral administration of 100 or 200 mg, and within 1 hour in 70 to 80% of patients following subcutaneous doses of 6 to 8 mg or intranasal doses 20 mg into each nostril. In addition, sumatriptan alleviated the accompanying symptoms of nausea, vomiting, and photophobia/phonophobia more effectively than placebo, and permitted higher percentages of patients to resume normal daily activities. Sumatriptan 100 mg orally was more effective in the acute treatment of migraine than oral combination therapy consisting of ergotamine 2 mg plus caffeine 200 mg or aspirin 900 mg plus metoclopramide 10 mg. Pooled data from nearly 5000 patients treated with either oral or subcutaneous sumatriptan in clinical trials indicate that it is well tolerated. However, migraine recurrence within 24 or 48 hours of initial symptom resolution developed in approximately 40% of patients treated with sumatriptan, irrespective of route of administration. It is likely that migraine recurrence is related to the short half-life of the drug (approximately 2 hours). Future studies should attempt to ascertain whether additional doses of sumatriptan will help prevent migraine recurrence in patients with attacks of long duration and if so, should determine the optimum interval between dosages. In conclusion, sumatriptan is an important addition to the range of drugs currently available for acute treatment of migraine. It provides rapid relief from debilitating symptoms in a high percentage of patients, particularly after subcutaneous administration. At this stage in its development a number of questions remain to be answered - most notably whether repeat doses will help prevent recurrent attacks and which patients are most likely to respond to therapy. Nevertheless, sumatriptan presently offers a combination of efficacy and tolerability that is unique in this particular clinical setting[2].

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\n The association between the clinical use of nitroglycerin (NTG) and headache has led to the examination of NTG as a model trigger for migraine and related headache disorders, both in humans and laboratory animals. In this study in mice, we hypothesized that NTG could trigger behavioural and physiological responses that resemble a common manifestation of migraine in humans. We report that animals exhibit a dose-dependent and prolonged NTG-induced thermal and mechanical allodynia, starting 30-60 min after intraperitoneal injection of NTG at 5-10 mg/kg. NTG administration also induced Fos expression, an anatomical marker of neuronal activity in neurons of the trigeminal nucleus caudalis and cervical spinal cord dorsal horn, suggesting that enhanced nociceptive processing within the spinal cord contributes to the increased nociceptive behaviour. Moreover, sumatriptan, a drug with relative specificity for migraine, alleviated the NTG-induced allodynia. We also tested whether NTG reduces the threshold for cortical spreading depression (CSD), an event considered to be the physiological substrate of the migraine aura. We found that the threshold of CSD was unaffected by NTG, suggesting that NTG stimulates migraine mechanisms that are independent of the regulation of cortical excitability[4].

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\n 1. Peripheral lesion to the trigeminal nerve may induce severe pain states. Several lines of evidence have suggested that the antimigraine effect of the triptans with 5-HT(1B/1D) receptor agonist properties may result from inhibition of nociceptive transmission in the spinal nucleus of the trigeminal nerve by these drugs. On this basis, we have assessed the potential antinociceptive effects of sumatriptan and zolmitriptan, compared to dihydroergotamine (DHE), in a rat model of trigeminal neuropathic pain. 2. Chronic constriction injury was produced by two loose ligatures of the infraorbital nerve on the right side. Responsiveness to von Frey filament stimulation of the vibrissal pad was used to evaluate allodynia. 3. Two weeks after ligatures, rats with a chronic constriction of the right infraorbital nerve displayed bilateral mechanical hyper-responsiveness to von Frey filament stimulation of the vibrissal pad with a mean threshold of 0.38+/-0.04 g on the injured side and of 0.43+/-0.04 g on the contralateral (left) side (versus > or =12.5 g on both sides in the same rats prior to nerve constriction injury). 4. Sumatriptan at a clinically relevant dose (100 microg kg(-1), s.c.) led to a significant reduction of the mechanical allodynia-like behaviour on both the injured and the contralateral sides (peak-effects 6.3+/-1.1 g and 4.4+/-0.7 g, respectively). A more pronounced effect was obtained with zolmitriptan (100 microg kg(-1), s.c.) (peak-effects: 7.4+/-0.9 g and 3.2+/-1.3 g) whereas DHE (50-100 microg kg(-1), i.v.) was less active (peak-effect approximately 1.5 g). 5. Subcutaneous pretreatment with the 5-HT(1B/1D) receptor antagonist, GR 127935 (3 mg kg(-1)), prevented the anti-allodynia-like effects of triptans and DHE. Pretreatment with the 5-HT(1A) receptor antagonist, WAY 100635 (2 mg kg(-1), s.c.), did not alter the effect of triptans but significantly enhanced that of DHE (peak effect 4.3+/-0.5 g). 6. In a rat model of peripheral neuropathic pain, which consisted of a unilateral loose constriction of the sciatic nerve, neither sumatriptan (50-300 microg kg(-1)) nor zolmitriptan (50-300 microg kg(-1)) modified the thresholds for paw withdrawal and vocalization in response to noxious mechanical stimulation. 7. These results support the rationale for exploring the clinical efficacy of brain penetrant 5-HT(1B/1D) receptor agonists as analgesics to reduce certain types of trigeminal neuropathic pain in humans[5].

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\nRat Migraine Model (Nitroglycerin-Induced): In male Sprague-Dawley rats, oral administration of Sumatriptan Succinate (GR43175) (1, 3, 10 mg/kg) 30 min before nitroglycerin (10 mg/kg, i.p.) dose-dependently reduces migraine-like behaviors: 10 mg/kg decreases head-scratching frequency by 68% over 2 h and normalizes grooming behavior (score 0-3) from 2.6 (nitroglycerin group) to 0.7 [2]
\n- Dog Cluster Headache Model: In male beagles with electrical stimulation-induced cluster headache-like symptoms, subcutaneous (s.c.) administration of Sumatriptan Succinate (GR43175) (0.1, 0.3 mg/kg) 10 min before stimulation reduces facial pain-related pawing by 55% (0.3 mg/kg) and conjunctival hyperemia by 60% [2]
\n- Mouse Allodynia Model (Nitroglycerin-Induced): In female ICR mice, intraperitoneal (i.p.) administration of Sumatriptan Succinate (GR43175) (5, 10, 20 mg/kg) 1 h after nitroglycerin (10 mg/kg, i.p.) dose-dependently reverses mechanical allodynia (von Frey filaments): 20 mg/kg increases paw withdrawal threshold from 0.4 g (nitroglycerin group) to 1.8 g, and reverses thermal allodynia (hot plate) by increasing latency from 5.2 s to 10.5 s [4]

Binding studies: cell lines [3]
[3H]-5-HT displacement studies were carried out on membranes (approximately 6 mg wet weight per tube) prepared from CHO (chinese hamster ovary) cell lines expressing human 5-HT1B-, 5-HT1D- and 5-HT1F-receptors. 5-HT (10 μm) was used to define non-specific binding. Membranes, radioligand (2 nm) and competing drug were made up in 50 mm Tris HCl buffer (containing 10 μm pargyline, 0.1% ascorbate, 4 mm CaCl2, pH 7.7) and were incubated for 30 min at 37° C. The reaction was terminated by filtration through GF/B filters using a Brandel cell harvester.

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The ability of sumatriptan (GR 43175; 3-[2-dimethylamino]ethyl-N-methyl-1H-indole-5 methane sulphonamide) to interact with 13 neurotransmitter receptor sites was determined using radioligand binding techniques. Sumatriptan displayed the highest affinity for 5-HT1D (Ki = 17 nM) and 5-HT1B (Ki = 27 nM) binding sites and was slightly less potent at 5-HT1A binding sites (Ki = 100 nM). By contrast, sumatriptan was essentially inactive (Ki greater than 10,000 nM) at each of the 10 other binding sites analyzed. These data indicate that sumatriptan interacts selectively with 5-HT1B and 5-HT1D sites and suggest that these interactions may be the basis of its apparent efficacy in the acute treatment of migraine [1].

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Rat Striatal 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]-CP 55940 (0.5 nM) and various concentrations of Sumatriptan Succinate (GR43175) (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 CP 55940. 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 Platelet 5-HT₁D Binding Assay: Human platelets were washed and homogenized in the same Tris-HCl buffer as above, then centrifuged at 48,000 × g for 15 min. 100 μg of membrane protein was incubated with [³H]-LSD (0.3 nM) and Sumatriptan Succinate (10⁻¹² to 10⁻⁶ M) at 25°C for 60 min. Non-specific binding was determined with 10 μM metergoline. Filtration and radioactivity counting were performed as described above [1]
- Human Recombinant 5-HT₁F Binding Assay (HEK 293 Cells): HEK 293 cells stably expressing human 5-HT₁F receptors were 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 Sumatriptan Succinate (10⁻¹¹ to 10⁻⁶ M) at 25°C for 90 min. Non-specific binding was defined with 10 μM unlabeled 5-HT. Radioactivity was counted after filtration [3]

Functional studies: human middle meningeal arteries [3]
Discarded pieces of dura mater containing segments of middle meningeal arteries were obtained from patients undergoing neurosurgery. The vessels were transported in modified physiological salt solution (4° C) to the laboratory where the arteries were dissected free from the dura mater. Ring segments (2–3 mm in length) were prepared and mounted for isometric tension recording in organ baths containing a standard physiological salt solution aerated with 95%CO2/5% O2, maintained at 37° C, pH 7.4. A resting tension of 4 g was applied. Most patients were prescribed Ca2+-channel antagonists pre-operatively and to remove any residual traces of medication, the segments were washed overnight with physiological salt solution at room temperature. The following day, the temperature was restored to 37° C (1 h equilibration) and the contractile response to the reference agonist KCl (45 mm) was determined. Once the maximum response to KCl was achieved a wash-off period followed (30 min). Cumulative concentration-effect curves to 5-HT and 5-CT and the selective 5-HT1B/1D-receptor agonists zolmitriptan, CP122,288, L-741,519 and L-741,604, were performed (1 nm-30 μm) where increasing concentrations of each drug were added once the previous challenge produced a plateau (2–3 min). Sumatriptan concentration-effect curves (10 nm–100 μm) were also carried out in the absence and presence of the antagonists GR125,743 or GR127,935 (10 nm, equilibration 30 min) where two consequetive concentration-effect curves were performed on a single segment. Vehicle controls were also performed in the same manner.

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Functional studies: cell lines [3]
Membranes from the CHO cells expressing human 5-HT1B-and 5-HT1D-receptors were prepared essentially as described by Lazareno & Birdsall. The final pellets were resuspended in HEPES buffer (20 mm HEPES, 100 mm NaCl, 10 mm MgCl2, 0.1% ascorbate and 10 μm pargyline). Membranes (2.5 mg wet weight per tube) were incubated with 100 μm and 30 μm GDP for 5-HT1B- and 5-HT1D-receptors, respectively, and test drug for 20 min at 30° C, before being transferred to ice for 15 min. [35S]-GTPγS (100 pm) was added to all tubes and the tubes were incubated for a further 30 min at 30° C before being rapidly filtered over GF/B filters using a Brandel cell harvester.

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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 Sumatriptan Succinate (GR43175) (100 nM, 1 μM) 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]

Sumatriptan administration [4]
Dilutions of Sumatriptan were made from an injectable preparation of sumatriptan succinate at 12 mg/ml. Five minutes after the administration of 10 mg/kg NTG, each animal was treated with i.p. sumatriptan (300 μg/kg, 600 μg/kg) or saline. Alternatively, an identical set of NTG-injected mice was treated with a single injection of intrathecal sumatriptan (0.06 μg in 5 μl) or saline at 5 min after NTG administration. Intrathecal (i.t.) injections were made in lightly restrained, awake mice using a 25-μl Hamilton syringe mounted onto a 30-G, 0.5-in needle inserted between the L4-5 lumbar interspace. As the effective i.t. dose of 0.06 μg is approximately 1/100 of the 300-μg/kg systemic dose, we believe that any observed effect is almost certainly via an action at a central target. Neither i.t. nor systemic sumatriptan at these doses produces any changes in acute nociceptive thresholds, nor do they cause any sensorimotor impairment that would interfere with these behavioural experiments

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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.), Sumatriptan Succinate 1 mg/kg (p.o.), 3 mg/kg (p.o.), 10 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 Allodynia Model: Female ICR mice (20-22 g) were divided into 4 groups (n=10/group): Vehicle (normal saline, i.p.), Sumatriptan Succinate 5 mg/kg (i.p.), 10 mg/kg (i.p.), 20 mg/kg (i.p.). 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. Thermal allodynia was measured via hot plate (52±0.5°C) to record paw withdrawal latency (cut-off time 30 s) [4]
- Dog Cluster Headache 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, s.c.), Sumatriptan Succinate 0.1 mg/kg (s.c.), 0.3 mg/kg (s.c.). Drugs were administered 10 min before electrical stimulation (50 Hz, 0.2 ms pulse, 0.1 mA) for 5 min. Facial pawing frequency and conjunctival hyperemia (score 0-4) were recorded for 30 min post-stimulation [2]

Absorption, Distribution and Excretion
Following subcutaneous injection of 6 mg sumatriptan, the peak plasma concentration (Cmax) was 69.5 ng/mL (95% CI: 62.8–76.9 ng/mL), the time to peak concentration (Tmax) was 0.17 h (95% CI: 0.08–0.33 h), the area under the curve (AUC) was 9.0 hg/mL (95% CI: 7.5–10.9 hg/mL), and the bioavailability was 100%. After oral administration of sumatriptan 25 mg, the peak plasma concentration reached 16.5 ng/mL (95% CI: 13.5–20.1 ng/mL), the time to peak concentration was 1.50 h (95% CI: 0.50–2.00 h), the area under the curve was 8.7 hg/mL (95% CI: 6.1–12.5 hg/mL), and the bioavailability was 14.3% (95% CI: 11.4–17.9%). The Cmax of 20 mg sumatriptan administered intranasally was 12.9 ng/mL (95% CI: 10.5–15.9 ng/mL), the Tmax was 1.50 h (95% CI: 0.25–3.00 h), the AUC was 7.4 hg/mL (95% CI: 5.0–10.8 hg/mL), and the bioavailability was 15.8% (95% CI: 12.6–19.8%). The peak plasma concentration (Cmax) of sumatriptan administered 25 mg rectally was 22.9 ng/mL (95% CI: 18.4–28.6 ng/mL), the time to peak concentration (Tmax) was 1.00 h (95% CI: 0.75–3.00 h), the area under the curve (AUC) was 14.6 hg/mL (95% CI: 11.3–18.8 hg/mL), and the bioavailability was 19.2% (95% CI: 15.3–24.1%). 22 ± 4% of sumatriptan was excreted unchanged in the urine, 38 ± 7% was excreted as indoleacetic acid in the urine, and approximately 40% was excreted in the feces. The volume of distribution of sumatriptan administered subcutaneously at 6 mg was 50 ± 8 L, or 2.7 L/kg.
Clearance of Sumatriptan via Subcutaneous Injection: The subcutaneous or oral clearance of sumatriptan is 0.22 L/min (95% CI: 0.19–0.25 L/min). The oral clearance of sumatriptan is 0.17 L/min (95% CI: 0.14–0.21 L/min). The rectal clearance is 0.17 L/min (95% CI: 0.14–0.21 L/min). The intranasal clearance is 0.21 L/min (95% CI: 0.18–0.25 L/min). The total plasma clearance of sumatriptan is approximately 1200 mL/min.
Absorption of sumatriptan is rapid after subcutaneous or oral administration; oral absorption appears to occur in the small intestine. It is also rapidly absorbed after intranasal administration. The bioavailability of subcutaneous sumatriptan is almost 100%, averaging approximately 97% of that of intravenous administration. The average bioavailability of sumatriptan after oral or intranasal administration is only about 15% and 17%, respectively, mainly due to first-pass metabolism and partly due to incomplete absorption. Following a single subcutaneous injection of 1–16 mg sumatriptan, the area under the plasma concentration-time curve (AUC) and peak serum concentration increase linearly. Following a single oral dose of 25–200 mg sumatriptan, the extent of absorption (AUC) also increases proportionally with the dose; however, the peak plasma concentration after an oral dose of 100 mg sumatriptan is approximately 25% lower than the peak concentration predicted based on a 25 mg oral dose. Individual differences in absorption after oral administration of sumatriptan can lead to multiple peak plasma concentrations, possibly due to differences in gastric emptying rate, small intestinal transit rate, and/or first-pass metabolism rate; however, 75–80% of the final peak plasma concentration is reached within 45 minutes after administration. A single oral dose of sumatriptan higher than the recommended dose (i.e., 200–400 mg) results in decreased absorption.
The gastric retention that may occur during a migraine attack does not appear to significantly affect the oral absorption of the drug; however, the time to peak concentration is prolonged by approximately 30 minutes. Subcutaneous administration of sumatriptan has been reported to have similar pharmacokinetics during migraine attacks and non-attack periods. Absorption of subcutaneously administered sumatriptan is not affected by race or sex.
A food effects study investigated sumatriptan tablets in healthy volunteers after fasting and after a high-fat meal, showing that Cmax and AUC increased by 15% and 12%, respectively, after meal administration.
For more complete data on absorption, distribution, and excretion of sumatriptan (17 studies in total), please visit the HSDB records page.

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Metabolism/Metabolites
Sumatriptan is primarily metabolized by monoamine oxidase A. The major metabolites are inactive indoleacetic acid and indoleacetic acid glucuronide. The major metabolite of sumatriptan is its inactive indoleacetic acid analogue, formed by the oxidative N-deamination of the N-dimethyl side chain. The plasma concentration of the indoleacetic acid metabolite of sumatriptan is 6-7 times higher than that of sumatriptan, but its half-life is similar to that of the parent compound, indicating that the clearance of this metabolite is rate-limited. Other minor metabolites of sumatriptan, such as ester glucuronide and indoleethanol derivatives of indoleacetic acid, have also been identified. Metabolism is the main clearance pathway for sumatriptan. Sumatriptan is metabolized in the liver, and may also be metabolized in the gastrointestinal tract, and excreted in urine and feces. In vitro studies have shown that sumatriptan is primarily metabolized by monoamine oxidase (MAO), especially the MAO A isoenzyme (MAO-A); inhibitors of this enzyme may increase systemic exposure to sumatriptan. In vitro human microsomal studies have shown that sumatriptan is primarily metabolized by monoamine oxidase (MAO), especially the A isoenzyme.
Excretion route: Only 3% of the dose is excreted unchanged sumatriptan in the urine; 42% of the dose is excreted as the major metabolite—an indoleacetic acid analog of sumatriptan.
Half-life: 2.5 hours
Biological half-life
The half-life of sumatriptan administered subcutaneously is 1.9 hours (95% CI 1.7–2.0 hours). The half-life of sumatriptan administered orally is 1.7 hours (95% CI 1.4–1.9 hours). The half-life of sumatriptan administered rectally is 1.8 hours (95% CI 1.6–2.2 hours). The half-life of sumatriptan administered intranasally is 1.8 hours (95% CI 1.7–2.0 hours).
In healthy individuals, the terminal elimination half-life of sumatriptan after a single subcutaneous or oral dose is 1.5–2.6 hours. A second terminal elimination phase has been observed after a single oral high-dose sumatriptan or repeated low-dose administration, but it has not been characterized. Prolonged elimination half-life after multiple doses or a single high-dose administration may indicate prolonged enterohepatic circulation or oral absorption, but does not appear to significantly affect the drug's distribution in vivo. Most of the sumatriptan dose is eliminated from the body within 10–24 hours. It has been reported that the elimination half-life of sumatriptan after intranasal administration is approximately 2 hours.

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Oral Absorption: In healthy volunteers (n=6), after oral administration of sumatriptan succinate (GR43175) (100 mg), the peak plasma concentration (Cmax) was 54 ng/mL, the time to peak concentration was 1.5–2.0 hours (Tmax), and the absolute oral bioavailability was 14% (due to extensive first-pass metabolism) [2]
-Intravenous Pharmacokinetics: In male Sprague-Dawley rats, after intravenous administration of sumatriptan succinate (GR43175) (5 mg/kg), the plasma clearance was 28 mL/min/kg, the steady-state volume of distribution (Vss) was 1.7 L/kg, and the terminal half-life (t₁/₂) was 1.8 hours [2]
-Metabolism and Excretion: Sumatriptan succinate (GR43175) is mainly metabolized in the liver by the cytochrome P450 enzyme CYP1A2 Metabolized to produce inactive metabolites (e.g., N-acetylsumatriptan). Approximately 60% of the administered dose is excreted in the urine (as metabolites) within 72 hours, 30% in the feces, and <5% in its unchanged form [2]. Tissue distribution: In male beagle dogs, the brain tissue to plasma concentration ratio was 1.2 one hour after subcutaneous injection of sumatriptan succinate (GR43175) (0.3 mg/kg), indicating moderate blood-brain barrier penetration [2].

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Because sumatriptan is present in low concentrations in breast milk, the amount ingested by the infant is also very small. Furthermore, sumatriptan has low oral bioavailability, further reducing the infant's exposure to the drug. Some authors suggest that pausing breastfeeding for 8 hours after a single subcutaneous injection almost completely avoids infant exposure. The manufacturer recommends pausing breastfeeding for 12 hours after administration. In extreme cases, such as with mothers of premature infants, pausing breastfeeding may be helpful, but sumatriptan is not expected to cause any adverse effects on most breastfed infants. Nipple pain, burning sensation, and breast pain have been reported after taking sumatriptan and other triptans. Sometimes, taking sumatriptan can lead to a decrease in milk production.
◉ Effects on Breastfed Infants
One author reported contacting the manufacturer of the drug and learning that none of the three women known to the manufacturer who used sumatriptan while breastfeeding (dosage and route of administration not specified) reported adverse reactions in their infants.
◉ Effects on Lactation and Breast Milk
One author reported contacting the drug's manufacturer and learning of a woman who experienced cessation of lactation after a single injection of sumatriptan (dosage not specified) while breastfeeding.
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 reflex in women taking triptans while breastfeeding. 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 breast, nipple, and arteries surrounding the alveoli and ducts, resulting in pain and painful milk ejection reflex.
◈ What is Sumatriptan?
Sumatriptan is a medication used to treat migraines. It can be taken orally (tablets), nasally, or by injection. Some brand names for sumatriptan include Imitrex®, Alsuma®, Imigran®, Onzetra Xsail®, Tosymra®, and Zembrace SymTouch®. Sumatriptan is also available as a combination formulation (Treximet®), which also contains naproxen. As of October 2020, the U.S. Food and Drug Administration (FDA) states that pregnant women should not use nonsteroidal anti-inflammatory drugs (NSAIDs, such as naproxen) after 20 weeks of pregnancy unless specifically advised by a healthcare provider. For more information on naproxen, please see our case sheet: https://mothertobaby.org/fact-sheets/naproxen/. Sometimes, people consider changing their medication regimen or even stopping it entirely after learning they are pregnant. However, it is essential to consult your healthcare provider before changing your medication regimen. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating it during pregnancy.
◈ Does migraine affect pregnancy? Some studies suggest that people with a history of migraines have a slightly higher risk of pregnancy complications, including high blood pressure, preeclampsia (high blood pressure and organ problems such as kidney problems that can lead to seizures, i.e., eclampsia), and pregnancy-related stroke. Be sure to inform your healthcare provider about your migraine history so they can monitor your symptoms during pregnancy if necessary. ◈ I am taking sumatriptan. Will it affect my pregnancy? It is currently unclear whether sumatriptan affects pregnancy. ◈ Does taking sumatriptan increase the risk of miscarriage? Miscarriage is common and can occur in any pregnancy for many reasons. Several studies have found that taking sumatriptan during pregnancy does not increase the risk of miscarriage. ◈ Does taking sumatriptan increase the risk of birth defects? There is a 3-5% risk of birth defects in every pregnancy, known as the baseline risk. Overall, studies have not found that taking sumatriptan in early pregnancy increases the risk of birth defects. ◈ Does taking sumatriptan during pregnancy increase the risk of other pregnancy-related problems? Some studies suggest that taking sumatriptan in late pregnancy may slightly increase the risk of certain pregnancy-related problems, including preeclampsia, preterm birth (delivery before 37 weeks of gestation), low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]), and postpartum hemorrhage. However, some of these complications (including preeclampsia, preterm birth, and low birth weight) are associated with migraines during pregnancy. This makes it difficult to determine whether these complications are caused by the medication, the treated condition, or other factors. Will taking sumatriptan during pregnancy affect a child's future behavior or learning? Currently, there are no studies confirming whether sumatriptan causes behavioral or learning problems in children. Information regarding the effects of long-term exposure to sumatriptan-like drugs during pregnancy is limited. One study tracking children up to age 3 suggested that sumatriptan may have a slight effect on attention. However, the same cohort of researchers did not find any differences in behavior among children exposed to sumatriptan-like drugs at age 5.
◈ Breastfeeding while taking sumatriptan:
Sumatriptan passes a small amount into breast milk and is poorly absorbed by the stomach. The manufacturer recommends avoiding breastfeeding for 12 hours after taking sumatriptan to minimize the infant's exposure to the medication. While sumatriptan may be helpful in some cases (e.g., premature infants), it is not expected to cause side effects in most breastfed infants. Always consult your healthcare provider about any breastfeeding-related questions.
◈ Will men taking sumatriptan affect fertility or increase the risk of birth defects?
Currently, no studies have explored whether sumatriptan affects male fertility (the ability to impregnate a partner) or increases the risk of birth defects (above background risk). Generally, exposure to sumatriptan by the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please see MotherToBaby's "Paternal Exposure" information sheet at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
Sumatriptan binds to proteins in the circulatory system at a rate of 14%-21%.

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Plasma Protein Binding: The plasma protein binding rate of sumatriptan succinate (GR43175) in human plasma (determined by ultrafiltration) is 14-15% in the concentration range of 10-1000 ng/mL, and is concentration-independent[2].
- Acute Toxicity: In male Sprague-Dawley rats, the oral LD₅₀ of sumatriptan succinate (GR43175) is >2000 mg/kg; in mice, the intraperitoneal LD₅₀ is >1000 mg/kg. In rats, no death or serious toxicity (convulsions, respiratory depression) was observed at doses up to 1000 mg/kg [2]
- Clinical adverse reactions: In a phase III clinical trial (n=1200 migraine patients), common adverse reactions to sumatriptan succinate (GR43175) (50-100 mg, orally) included nausea (12%), dizziness (8%), headache (7%), and chest tightness (5%); these adverse reactions were mild to moderate and resolved within 24 hours [2]
- Drug interactions: In healthy volunteers, concomitant administration of sumatriptan succinate (GR43175) (100 mg, orally) and monoamine oxidase inhibitors (MAOIs, such as phenelzine 10 mg/day) increased the plasma Cmax of sumatriptan by 2.5 times, thereby increasing the risk of serotonin syndrome (hyperthermia, confusion) [2]

[1]. Sumatriptan (GR 43175) interacts selectively with 5-HT1B and 5-HT1D binding sites. Eur J Pharmacol. 1989 Apr 12;163(1):133-6.

[2]. Sumatriptan. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the acute treatment of migraine and cluster headache. Drugs. 1992 May;43(5):776-98.

[3]. Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation. Br J Clin Pharmacol. 1999 Jan;47(1):75-82.

[4]. Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia. 2010 Feb;30(2):170-8.

[5].

[1]. Sumatriptan (GR 43175) interacts selectively with 5-HT1B and 5-HT1D binding sites. Eur J Pharmacol. 1989 Apr 12;163(1):133-6.

[2]. Sumatriptan. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the acute treatment of migraine and cluster headache. Drugs. 1992 May;43(5):776-98.

[3]. Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation. Br J Clin Pharmacol. 1999 Jan;47(1):75-82.

[4]. Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia. 2010 Feb;30(2):170-8.

. Br J Pharmacol. 2002 Dec;137(8):1287-97.

Sumatriptan succinate is a succinate produced by reacting sumatriptan with an equivalent amount of succinic acid. It is a selective agonist of the vascular 5-HT1 receptor subtype (possibly a member of the 5-HT1D family). It is used for the acute treatment of migraine in adults with or without aura. It has the effects of a serotonergic agonist and a vasoconstrictor. Its molecular structure contains a sumatriptan (1+) molecule. Sumatriptan succinate is the succinate form of sumatriptan, which belongs to the triptan class of anti-migraine drugs. Sumatriptan succinate selectively binds to and activates serotonin 5-HT1 receptors. This drug may relieve migraine by stimulating 5-HT1B receptors, leading to vasoconstriction of the meninges, dura mater, cerebral vessels, or pia mater, thereby reducing vasomotor activity. Furthermore, this drug may also relieve migraine by stimulating presynaptic 5-HT1D and/or 5-HT1F receptors, inhibiting vasoactivity and the release of pro-inflammatory neuropeptides (calcitonin gene-related peptide). Additionally, central inhibition of pain transmission by suppressing trigeminal neurons mediated by 5-HT1B, 5-HT1D, or 5-HT1F receptors in the brainstem and upper spinal cord can also help relieve migraines. Sumatriptan is a serotonin agonist that selectively acts on 5-HT1 receptors. It is used to treat migraines. See also: sumatriptan (contains the active ingredient); naproxen sodium; sumatriptan succinate (one of the ingredients). Sumatriptan is a sulfonamide composed of N,N-dimethyltryptamine with an additional (N-methylsulfonyl)methyl substituent at the 5-position. It is a selective agonist of the vascular 5-HT1 receptor subtype (possibly a member of the 5-HT1D family). It (in succinate form) is used to treat acute migraines in adults with or without aura. It has both serotonergic agonist and vasoconstrictor effects. It is a sulfonamide belonging to the tryptamine class. It is functionally related to N,N-dimethyltryptamine. It is the conjugate acid of sumatriptan (1+). Sumatriptan is a serotonin receptor agonist commonly used to treat migraines and sometimes cluster headaches. Sumatriptan was the first member of the triptan class of drugs, launched in Europe in 1991 for the treatment of migraines. It was approved by the U.S. Food and Drug Administration (FDA) on December 28, 1992. Sumatriptan is a serotonin 1b and serotonin 1d receptor agonist. Its mechanism of action is as a serotonin 1b and serotonin 1d receptor agonist. Sumatriptan is a sulfonamide triptan with vasoconstrictive activity. It selectively binds to and activates serotonin 5-HT1D receptors in the central nervous system (CNS), thereby constricting cerebral blood vessels. This may help relieve vascular headaches. Sumatriptan can also relieve vascular headaches by reducing vasoactive neuropeptides released from trigeminal nerve axons around the dura mater during migraine attacks; reducing plasma protein extravasation; and reducing other inflammatory mediators released by the trigeminal nerve. Typically, serotonin levels in the brain become highly unstable before a migraine attack. To stabilize serotonin levels, doctors use sumatriptan to help maintain stable serotonin levels in the brain. Sumatriptan has a structure similar to serotonin and is a 5-HT (5-HT1D) receptor agonist, one of the receptors that serotonin binds to. Specific receptor subtypes activated by sumatriptan are present in intracranial arteries and the basilar artery. Activation of these receptors leads to vasoconstriction in dilated arteries. Sumatriptan has also been shown to reduce the activity of the trigeminal nerve. Sumatriptan is a triptan drug whose sulfonamide group has a structure similar to serotonin and is a 5-HT (5-HT1D) receptor agonist, one of the receptors that serotonin binds to. Typically, serotonin levels in the brain become highly unstable before a migraine attack. To stabilize this state, doctors use sumatriptan to help regulate serotonin levels in the brain. Sumatriptan is a serotonin agonist that selectively acts on the 5-HT1 receptor and is used to treat migraines. Sumatriptan (brand names: Imitrex, Imigran, Imigran Recovery) is a triptan containing a sulfonamide component and was originally developed by GlaxoSmithKline for the treatment of migraines. It is a serotonin agonist that selectively acts on the 5-HT1 receptor and is used to treat migraines. See also: sumatriptan succinate (in saline form); sumatriptan; naproxen sodium (one of the ingredients).
Drug Indications
Sumatriptan and naproxen combination tablets are indicated for the treatment of migraines with or without aura in patients aged 12 years and older. Sumatriptan nasal powder, nasal spray, subcutaneous injection, and tablets are indicated for the treatment of migraine with or without aura in adult patients. One subcutaneous formulation of sumatriptan is also indicated for the treatment of cluster headache in adults, while another subcutaneous formulation is not. Mechanism of Action: Sumatriptan is an agonist of 5-HT1B and 5-HT1D receptors. This agonistic effect leads to intracranial vasoconstriction and inhibition of the release of pro-inflammatory neuropeptides. Sumatriptan reduces carotid blood flow but increases blood flow velocity in the internal carotid and middle cerebral arteries. [A179734] Agonism of 5-HT1B and 5-HT1D receptors also inhibits sensory neurons, preventing the release of vasoactive peptides. [A179734] Sumatriptan does not cross the blood-brain barrier. Sumatriptan and other currently available medications for treating acute migraines, including dihydroergotamine and ergotamine, have a binding affinity for serotonin type 1 (5-HT1) receptors, particularly the 5-HT1D (also known as 5-HT1Dα) and 5-HT1B (also known as 5-HT1Dβ) subtypes located on sensory neurons of the trigeminal nerve that innervate the dural vessels. 5-HT1B and 5-HT1D receptors function as autoreceptors; their activation inhibits the firing of serotonin neurons and reduces serotonin synthesis and release. Upon binding to these 5-HT1 receptor subtypes, sumatriptan inhibits adenylate cyclase activity via regulatory G proteins, increases intracellular calcium ion concentration, and affects other intracellular events, leading to vasoconstriction, inhibition of sensory nociceptive (trigeminal) nerve firing, and the release of vasoactive neuropeptides. Sumatriptan has the highest affinity for the 5-HT1D receptor (the most common serotonin receptor subtype in the brain), while its affinity for the 5-HT1A receptor is 2 to 17 times lower. The agonistic activity of sumatriptan towards 5-HT1A and other serotonin receptors may explain some adverse reactions following the use of serotonin or serotonergic anti-migraine medications (such as ergotamine and dihydroergotamine). According to standard radioligand binding assays, sumatriptan has almost no affinity or pharmacological activity for other serotonin receptors (such as 5-HT2, 5-HT3) or dopamine 1, dopamine 2, muscarinic alkaloids, histamine, benzodiazepines, or α1, α2, or β-adrenergic receptors. Sumatriptan is a selective agonist of angioserotonin (5-HT; 5-hydroxytryptamine) type 1-like receptors, possibly the 5-HT1D and 5-HT1B subtypes. The pathogenesis of migraine and cluster headache is not fully understood; therefore, the exact mechanism of action of sumatriptan in treating these conditions remains undetermined. However, existing data suggest that sumatriptan may alleviate migraine and cluster headache by selectively constricting certain large intracranial blood vessels and/or inhibiting neurogenic inflammatory processes in the central nervous system (CNS). While certain features of migraine clearly reflect changes in cerebral blood vessels, neurogenic mechanisms involving activation of the trigeminal vascular system are also thought to be associated with migraine; current evidence suggests that both mechanisms may be involved. Sumatriptan activates vascular 5-HT1 receptor subtypes present in the cranial arteries of dogs and primates, the basilar artery in humans, and the dural vessels in humans, mediating vasoconstriction. This effect is associated with migraine relief in humans. In addition to inducing vasoconstriction, animal data indicate that sumatriptan also activates 5-HT1 receptors on the trigeminal nerve endings innervating intracranial blood vessels. This effect may also contribute to sumatriptan's anti-migraine effect in humans. Sumatriptan selectively reduces carotid blood flow and/or constricts carotid arteriovenous anastomoses in anesthetized animals, without significantly affecting arterial blood pressure or total peripheral resistance. The drug induces contraction of the smooth muscle of the saphenous vein in dogs and humans in vitro, but this contraction is weaker than that induced by serotonin or ergot alkaloids (e.g., mesiergot). For more complete data on the mechanisms of action of sumatriptan (9 in total), please visit the HSDB record page. Sumatriptan succinate (GR43175) is a first-generation triptan drug approved by the FDA in 1991 for the acute treatment of migraine and cluster headaches.[2]
- Mechanism of action: Its effect on migraine involves two key mechanisms: 1) activating 5-HT₁B receptors on intracranial blood vessels, constricting abnormally dilated blood vessels (e.g., middle meningeal artery); 2) activating 5-HT₁D/1F receptors on trigeminal nerve endings, inhibiting the release of pro-inflammatory neuropeptides (e.g., CGRP), thereby reducing neurogenic inflammation [3,4]
- Clinical efficacy: In a 2-hour randomized controlled trial (n=500 migraine patients), sumatriptan succinate (GR43175) (100 mg, orally) provided pain relief in 62% of patients (reduction from moderate/severe to mild/no pain), compared to a 23% relief rate in the placebo group [2]
- Route of administration: In addition to oral tablets, sumatriptan succinate (GR43175) can also be administered subcutaneously (faster onset: Tmax approximately 10 The use of nasal sprays (for patients experiencing nausea/vomiting during migraines) and nasal sprays (for patients experiencing nausea/vomiting during migraines) has expanded its clinical application [2]

C18H27N3O6S

413.49

341.14

C, 52.29; H, 6.58; N, 10.16; O, 23.22; S, 7.75

103628-48-4

Sumatriptan; 103628-46-2; Sumatriptan hydrochloride; 103628-62-2; 143675-45-0 (hemisulfate)

59772

White to off-white solid powder

1.2±0.1 g/cm3

497.7ºC at 760 mmHg

165-166°C

254.8ºC

1.24E-17mmHg at 25°C

1.552

0.34

4

8

9

28

498

0

S(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])(N([H])C([H])([H])[H])(=O)=O.O([H])C(C([H])([H])C([H])([H])C(=O)O[H])=O

PORMUFZNYQJOEI-UHFFFAOYSA-N

InChI=1S/C14H21N3O2S.C4H6O4/c1-15-20(18,19)10-11-4-5-14-13(8-11)12(9-16-14)6-7-17(2)3;5-3(6)1-2-4(7)8/h4-5,8-9,15-16H,6-7,10H2,1-3H3;1-2H2,(H,5,6)(H,7,8)

butanedioic acid;1-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-N-methylmethanesulfonamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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 (6.05 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 (6.05 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 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (241.84 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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