Mechanism of Action: Sumatriptan has been demonstrated to be a selective agonist for a vascular 5-hydroxytryptamine₁ receptor subtype (probably a member of the 5-HT_1D family) with no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT₂, 5-HT₃ receptor subtypes or at alpha_1-, alpha_2-, or beta-adrenergic; dopamine₁; dopamine₂; muscarinic; or benzodiazepine receptors.

The vascular 5-HT₁ receptor subtype to which sumatriptan binds selectively, and through which it presumably exerts its antimigrainous effect, has been shown to be present on cranial arteries in both dog and primate, on the human basilar artery, and in the vasculature of the isolated dura mater of humans. In these tissues, sumatriptan activates this receptor to cause vasoconstriction, an action in humans correlating with the relief of migraine and cluster headache. In the anesthetized dog, sumatriptan selectively reduces the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. In the cat, sumatriptan selectively constricts the carotid arteriovenous anastomoses while having little effect on blood flow or resistance in cerebral or extracerebral tissues.

Corneal Opacities: Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dosage tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established; however, the relative exposure at the lowest dose tested was approximately 5 times the human exposure after a 100-mg oral dose or 3 times the human exposure after a 6-mg subcutaneous dose.

Melanin Binding: In rats with a single subcutaneous dose (0.5 mg/kg) of radiolabeled sumatriptan, the elimination half-life of radioactivity from the eye was 15 days, suggesting that sumatriptan and its metabolites bind to the melanin of the eye. The clinical significance of this binding is unknown.

Pharmacokinetics: Pharmacokinetic parameters following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age, 33 years; mean weight, 77 kg) were systemic clearance: 1,194 ± 149 mL/min (mean ± S.D.), distribution half-life: 15 ± 2 minutes, terminal half-life: 115 ± 19 minutes, and volume of distribution central compartment: 50 ± 8 liters. Of this dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the indole acetic acid metabolite.

After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age, 24 ± 6 years; weight, 70 kg), the maximum serum concentration (C_max) was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (T_max) was 12 minutes after injection (range, 5 to 20 minutes). In this study, the same dose injected subcutaneously in the thigh gave a C_max of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The T_maxoramount absorbed was not significantly altered by either the site or technique of injection.

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