Sumatriptan is believed to constrict selectively the cranial vessels that are distended and inflamed during migraine. The action is mediated by activation of a 5-HT₁ receptor subtype which has been shown in animals to be localized in cranial vessels. Further studies to elaborate sumatriptan’s precise clinical mode of action have focused on the human meningeal circulation and should lead to a better understanding of the pathogenesis of migraine. Administering [¹⁴C]sumatriptan, drug-related material was shown to be well absorbed. Following absorption there was some first-pass metabolism resulting in oral bioavailabilities of 37, 58 and 23% in rat, dog and rabbit, respectively. In all species, circulating sumatriptan was cleared rapidly by metabolic and renal clearance with a half-life of 1–2 h. The indoleacetic acid metabolite is the primary metabolic product; however, rats, mice and rabbits also N-demethylate the methylaminosulphonylmethyl side-chain. The passage of sumatriptan and its metabolites across the blood-brain barrier appeared to be very limited, although some drug could be detected in the cerebrospinal fluid after administration of high intravenous doses. Safety studies in various animal species showed that sumatriptan produced few adverse pharmacodynamic effects when administered acutely, except at high doses, although it was less well tolerated in dogs. No findings of toxicological significance were observed in rats and dogs after chronic dosing for 1 year or more. The highest doses used in both acute and chronic toxicology studies were limited by behavioural effects but there were no pathological changes. In rats and rabbits sumatriptan had no adverse effects on reproduction and there was no evidence of genotoxicity. Long-term exposure did not induce any treatment-related increase in the incidence of tumours in mice or rats.

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1 Sumatriptan is a potent and selective 5-HT1 receptor agonist marketed for the treatment of migraine by both oral and subcutaneous routes. An extensive toxicologi cal programme employing high doses of sumatriptan was carried out in a range of animal species. The stud ies evaluated both the local and systemic tolerance to single and repeated dosing, effects on all stages of repro duction, as well as the genotoxic and oncogenic poten tial of sumatriptan. 2 The administration of relatively high single and repeat ed doses of sumatriptan was well tolerated by both rodents and dogs by the oral, subcutaneous and intra venous routes. Behavioural effects, suggestive of involvement of the central nervous system, were the most obvious result of such doses and were generally more pronounced in dogs than rodents. The reason for this may be related to the higher plasma concentrations of the drug achievable in dogs. Additional observations restricted to dogs, were transient, and included tachy cardia, facial oedema and breaks in the continuity of secretion films on the corneal surface. A tendency for an increase in weight gain was seen for rats, while a slight decrease was usually seen for dogs. The only pathologi cal changes related to treatment with high concentra tions of sumatriptan consisted of local reactions at the site of subcutaneous administration. 3 Sumatriptan is an indole; the structures of this chemical class show varying propensities for nitrosation. However, appropriate testing with sumatriptan failed to identify any mutagenic nitroso compounds. 4 Sumatriptan was neither genotoxic nor oncogenic. 5 Reproductive studies demonstrated that sumatriptan was not teratogenic and had no effect on peri- and post natal development. Some embryotoxicity was observed, but only at maternally toxic doses. A slight decrease in the success of insemination was also noted at high oral doses in rats. 6 Results of the toxicological programme performed in support of migraine therapy with sumatriptan provide good assurance of safety for subcutaneous and oral use.