Mode of action of the anti-migraine drug sumatriptan

Humphrey, P. P. A.; Feniuk, W.

doi:10.1016/0165-6147(91)90630-b

Cited by 237 publications

(140 citation statements)

References 31 publications

Supporting

Mentioning

139

Contrasting

Unclassified

Order By: Relevance

“…to inhibit release of the neuropeptides (CGRP and substance Introduction P) from perivascular trigeminal sensory neurones [2,3]. 5HT 1D receptors have also been shown to modulate Zolmitriptan (311C90, (S)-4[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl ]methyl-2-oxazolidinone) is a potent and nociceptive input at the level of the trigeminal nucleus caudalis, suggesting that central sites may represent an highly selective 5HT 1D receptor agonist in development for the acute treatment of migraine [1].…”

mentioning

confidence: 99%

The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90)

Seaber

Dixon

et al. 1997

Brit J Clinical Pharma

View full text Add to dashboard Cite

Aims Two open studies in healthy volunteers were conducted to determine the absolute bioavailability and metabolic disposition of zolmitriptan (311C90), a novel 5HT 1D agonist for the acute treatment of migraine. Methods After an initial test i.v. infusion, bioavailabilty was assessed by comparison of AUC after an i.v. infusion (3.5 mg ) and an oral tablet (10 mg), in six men and six women using a randomised, crossover design. Disposition was studied by administration of a 25 mg capsule, labelled with 100 mCi [ 14 C]-zolmitriptan, to five men and one woman on a single occasion. Results Zolmitriptan was well tolerated by both i.v. and oral routes. Adverse events were mostly mild, consistent with earlier studies and characteristic of this class of drug. Reports were similar in nature and number after both oral and iv dosing. Mean±s.d. oral bioavailability was 0.49±0.24 (0.38±0.16 in men and 0.60±0.28 in women). After oral dosing, C max and AUC values in women were approximately double those in men. Relative to zolmitriptan concentrations, metabolite concentrations were higher after oral dosing than after i.v., and higher in men compared with women. Half-life was significantly longer after oral dosing (mean 22%, 95% CI 6-35%). Mean±s.d. values for CL, V z and t 1/2,z after i.v. dosing (all subjects) were 8.7±1.7 ml min −1 kg −1 , 122±32 l and 2.30±0.59 h respectively. Following administration of 25 mg [ 14 C]-zolmitriptan, 91.5% of the dose was recovered in 7 days, 64.4±6.5% in urine and 27.1±6.0% in faeces. Less than 10% was recovered unchanged in urine, with 31.1±6.4% recovered as the inactive indole acetic acid metabolite. Most of the faecal material was unchanged zolmitriptan, representing unabsorbed drug. Plasma concentrations of [ 14 C] were slightly higher than those of the summed concentrations of known analytes zolmitriptan, the active N-desmethyl metabolite (183C91), the inactive N-oxide (1652W92) and indole acetic acid (2161W92) metabolites, which accounted for 86% of total plasma radioactivity. No other significant metabilites were detected in plasma. Some minor additional metabolites were detected in urine, none of which contributed more than 5% of the dose. Conclusions The data suggest that zolmitriptan undergoes first-pass metabolism and this is more extensive in men than in women. Zolmitriptan has suitable bioavailabilty for an acute oral migraine treatment and there are no significant unidentified metabolites in man.

show abstract

mentioning

confidence: 99%

The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90)

Seaber

Dixon

et al. 1997

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Moreover, the potency with which substance P increased pial artery diameter in the guinea-pig was similar to that observed in cat cerebral vessels (Edvinsson et al, 1981;Jansen et al, 1991). Such a vasodilatation could activate trigeminal nerve endings and via the initiation of local axon reflexes lead to the sensation of pain (Humphrey & Feniuk, 1991).…”

Section: Discussionmentioning

confidence: 57%

“…Substance P causes both local oedema and plasma protein extravasation by increasing vascular permeability (Markowitz et al, 1987) and, in common with CGRP, produces vasodilatation of the intracranial vasculature (Edvinsson et al, 1981;McCulloch et al, 1986). This vasodilatation may result in the initiation of local axon reflexes and thus further activation of trigeminal perivascular sensory nerves contributing to the perception of pain (Humphrey & Feniuk, 1991).…”

Section: Introductionmentioning

confidence: 99%

Neurokinin‐induced changes in pial artery diameter in the anaesthetized guinea‐pig

Beattie¹,

Stubbs²,

Connor³

et al. 1993

British J Pharmacology

View full text Add to dashboard Cite

1 The effects of selective neurokinin agents on pial artery diameter, measured with an on-line image analyser, have been studied in anaesthetized guinea-pigs in order to characterize the neurokinin receptors present on pial arteries. 2 Perivascular injection of either substance P (0.01-1 M) or the selective NK, receptor agonists, substance P methyl ester (SPOMe, 0.01-1 LM) and GR73632 (0.1 JM), increased pial artery diameter.3 In contrast, the selective NK2 receptor agonist, GR64349 (1 gM), produced a small vasoconstriction while the NK3 receptor-selective agonist, senktide (1 JM) was inactive.4 Co-administration of GR82334 (1 AM), a selective NKI receptor antagonist, inhibited the vasodilatation produced by SPOMe (0.1 JM) but not that caused by calcitonin gene-related peptide (CGRP, 0.01 AM).5 The results are consistent with an involvement of NK, receptors in the neurokinin-induced increase in guinea-pig pial artery diameter.

show abstract

“…Findings by Kaumann et al (1994) generally support this conclusion although they also showed that in many cases contractions to 5-HT were mediated predominantly by 5-HT1- Noradrenaline (-log M) Figure 6 The effect of IOJM sodium nitroprusside (SNP) on the contraction curves to (a) 5-HT, (b) sumatriptan, (c (Golino & Maseri, 1994) and the use of selective and potent 5-HTI-like agonists (e.g. sumatriptan) for the treatment of migraine (Humphrey & Feniuk, 1991 The ability of a receptor-linked agonist to overcome functional antagonism depends on its receptor density, affinity ofthe agonist for the receptor as well as the efficiency and type ofsignal transduction system involved. Thus, in the present study, SNP completely abolished the contraction curves to sumatriptan and methysergide, whilst only suppressing that to the 7 fold more potent 5-HT1-like receptor agonist, 5-HT (in the presence of ketanserin) by approximately 70%.…”

Section: Dog Lateral Saphenous Veinmentioning

confidence: 81%

Effects of U46619 on contractions to 5‐HT, sumatriptan and methysergide in canine coronary artery and saphenous vein in vitro

Kemp

Cocks

1995

British J Pharmacology

View full text Add to dashboard Cite

1 The aim of this study was to investigate the mechanism of enhanced reactivity to 5-hydroxytryptamine (5-HT) and sumatriptan previously observed in human isolated coronary arteries when active force was raised with the thromboxane A2-mimetic, U46619. 2 Ring segments of dog isolated coronary artery and saphenous vein were suspended in organ baths and cumulative concentration-contraction curves to 5-HT, sumatriptan and methysergide were constructed in the absence and presence of low concentrations of U46619. 3 In both endothelium-intact and endothelium-denuded rings of coronary artery, precontraction with U46619 to low (< 10% F..; the contraction to a maximum depolarizing 125 mM KCl Krebs solution; KPSS) levels of active force had no effect on either the maximum contraction or sensitivity (pECmo) to 5-HT, sumatriptan and methysergide. 4 Ketanserin (1 pM) had no effect on contractions to sumatriptan and methysergide in endotheliumdenuded coronary artery rings, but reduced the maximum contraction to 5-HT by z 90% to a value (5% F) similar to that for sumatriptan and methysergide. Under these conditions, U46619 precontraction had no effect on either pECm or maximum for 5-HT, sumatriptan or methysergide.5 In rings of saphenous vein with endothelium and treated with ketanserin (1 pM), 5-HT and sumatriptan caused equal maximum responses of 65% F.. which were approximately double that of methysergide (32% F..). The maximum responses and sensitivity to 5-HT, sumatriptan, methysergide and noradrenaline were unaffected by precontraction with U46619. 6 Pretreatment of the saphenous vein with sodium nitroprusside (SNP; 10 kiM) caused a small sustained relaxation and significantly depressed the maximal contraction to 5-HT without affecting sensitivity and abolished the contraction curve to sumatriptan and methysergide. When the relaxation response to SNP was reversed with U46619 (1-4 nM), the contraction curves to 5-HT, sumatriptan and methysergide were similar to those obtained prior to relaxation with SNP. In contrast, the same treatment with SNP had little affect on the contraction curve to noradrenaline. 7 In conclusion, the pattern of U46619-enhanced reactivity of 5-HT, sumatriptan and methysergide in SNP-treated dog saphenous vein, highlights the importance of functional antagonism when assessing reactivity to contractile agonists in isolated blood vessels.

show abstract

Mode of action of the anti-migraine drug sumatriptan

Cited by 237 publications

References 31 publications

The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90)

The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90)

Neurokinin‐induced changes in pial artery diameter in the anaesthetized guinea‐pig

Effects of U46619 on contractions to 5‐HT, sumatriptan and methysergide in canine coronary artery and saphenous vein in vitro

Contact Info

Product

Resources

About