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.

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The preclinical toxicological evaluation of sumatriptan