Reference

Absorption, pharmacokinetics and metabolism of 14C-sumatriptan following intranasal administration to the rat

Absorption, pharmacokinetics and metabolism of 14C-sumatriptan following intranasal administration to the rat. Ayres, D. W.; Barrow, A.; Scully, N. L.; Curtis, G. C.; Hughes, H. M. (Int. BioMet Div., GlaxoWellcome Res. Development, Ware SG12 0DP, UK). Xenobiotica, 26(12), 1273-1282 (English) 1996 Taylor & Francis. CODEN: XENOBH. ISSN: 0049-8254. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Studies have been carried out to investigate the absorption of sumatriptan after intranasal administration to rats. The pharmacokinetics, metab. and excretion of 14C-sumatriptan were compared following intranasal and i.v. dosing to male and female albino rats using an aq. buffered formulation at pH 5.5. Following i.v. administration sumatriptan was eliminated from plasma with a half-life of about 1.1 h. After intranasal administration there was rapid absorption of part of the dose and two peak plasma concns.Several substances with their cas registry numbers 103628-46-2 and 103628-44-0 may be metioned in this study. were obsd., initially at 0.5 and then at 1.5-2 h. The elimination half-life after the second peak was estd. as being about 4 h. Radioactivity was largely excreted in urine (up to 89% of dose in 168 h) after both i.v. and intranasal administration, with a faster rate of excretion after i.v. dosage (75% males, 64% females within 6 h) than after intranasal dosage (37% males, 40% female within 6 h). 14C-sumatriptan was the major component in urine and in exts. of feces after both i.v. and intranasal administration. The major metabolite excreted in urine and feces was GR49336, the indole acetic acid analog. The results of this in vivo rat study suggested that absorption of the dose via the nasal mucosa is incomplete after intranasal administration and that there is a secondary absorption phase probably reflecting oral absorption of part of the dose. The bioavailability is estd. as about 30%, for the period 0-6 h. .

The central cholinergic system has a role in the antinociception induced in rodents and guinea pigs by the antimigraine drug sumatriptan

The central cholinergic system has a role in the antinociception induced in rodents and guinea pigs by the antimigraine drug sumatriptan. Ghelardini, Carla; Galeotti, Nicoletta; Figini, Michela; Imperato, Assunta; Nicolodi, Maria; Sicuteri, Federigo; Gessa, Gian Luigi; Bartolini, Alessandro (Dep. Preclinical Clinical Pharmacol., Univ. Florence, Florence, Italy). Journal of Pharmacology and Experimental Therapeutics, 279(2), 884-890 (English) 1996 Williams & Wilkins. CODEN: JPETAB. ISSN: 0022-3565. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The antinociceptive effect of the antimigraine drug sumatriptan was assessed in mice and rats (hot-plate, abdominal constriction and paw-pressure tests) and in guinea pigs (paw-pressure test). The ACh extracellular concn. also was detected in the hippocampus of freely moving rats by microdialysis expts. Antinociception was induced by sumatriptan administered both parenterally (5-10 mg×kg-1 i.v.; 10-30 mg×kg-1 i.p.) and i.c.v. (50-100 mg per mouse). Sumatriptan antinociception was potentiated by physostigmine (0.05 mg×kg-1 i.p.) and was prevented by the muscarinic antagonist atropine (5 mg×kg-1 i.p.), the ACh depletor HC-3 (1 mg per mouse i.c.v.) and the 5-hydroxytryptamine1A antagonist 1-(2-methoxyphenyl)-4-[4-(2 phthalimido)butyl]piperazine (0.5 mg×kg-1, i.p.). Naloxone, 3-aminopropyl-diethoxy-methyl-phosphinic acid, 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino) Et ester and reserpine, administered in doses suitable for blocking analgesia induced by morphine, baclofen, 5-hydroxytryptamine4 agonists and clomipramine, resp., did not modify sumatriptan antinociception. Sumatriptan, administered in the range of antinociceptive doses, was able to increase the level of ACh present in extracellular hippocampal space. On the basis of these findings, we can deduce that sumatriptan was able to induce antinociception by increasing cholinergic activation in the CNS. 51-84-3 and 103628-46-2 are just another two chemicals used in this study. Such activation, as indicated by the antagonism exerted by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine, may depend on stimulation of 5-hydroxytryptamine1A autoreceptors. It remains to be clarified whether the antimigraine activity of sumatriptan in humans is totally dependent on cranial vessel vasoconstriction or whether its central cholinergic antinociception also plays a role. .