Preclinical Studies on the Anti-Migraine Drug, Sumatriptan

Abstract

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.

Where do triptans act in the treatment of migraine?

“…But the relatively low brain penetration of sumatriptan called into question whether CNS effects were at all necessary for its antimigraine activity (Humphrey et al, 1991). Disruption of the blood-brain barrier by hyperosmolar mannitol infusion was used to study possible CNS actions of sumatriptan.…”

The effects of oral sumatriptan, a 5‐HT1 receptor agonist, on circulating ACTH and cortisol concentrations in man.

“…It is virtually devoid of 5-HT2 and 5-HT3 activity [9]. Radioligand and binding studies [29] have shown it to have highest affinity for the 5-HTlD receptor subtypes and weaker affinity at the 5-HTlA subtype (pKD, 7.54 and 6.13, 5-HTID and 5-HTlA, respectively).…”

“…Activation of pre-synaptic auto-inhibitory receptors at this site would reduce the release of CRF and hence ACTH. 5-HTID receptors have been demonstrated to occur in low levels in the hypothalamus [33], suggesting that this may be a possible site of action for sumatriptan, although studies in several species have shown that the passage of sumatriptan and its metabolites across the BBB is very limited [9,30].…”

“…It has recently been introduced for the treatment of migraine [8]. It appears to act at a 5-HT1 receptor subtype similar to the 5-HTlD receptor [9]. In an earlier unpublished pilot study, sumatriptan reduced the circulating cortisol concentrations in healthy volunteers (data on file).…”

Skin Irritation, Skin Sensitization and in Vivo Studies of Sumatriptan Succinate New Liposomal Drug in Adhesive Patch for Transdermal Drug Delivery

“…[11] According to U.S. half-lives of the active ingredient. [10][11][12][13] Time periods between sampling mustn't exceed one terminal half-life. [14] From the pharmacokinetic data reported in the existing literature, it absolutely was found that the halflife (t1/2) of sumatriptan is close to 1 to 2 h. [15] Hence, in the present study, the samples were collected up to 12 h after drug administration as to cover a minimum of 3 half lives of the sumatriptan.…”