The tolerability and pharmacokinetics of the novel antimigraine compound 311C90 in healthy male volunteers

Seaber, Emma J.; On, N.T.; Phillips, Steven E.; Churchus, Richard; Posner, John; Rolan, P.

doi:10.1111/j.1365-2125.1996.tb00172.x

Cited by 54 publications

(45 citation statements)

References 7 publications

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“…There was, however, little information on the reason for this. Interestingly, Seaber et al (1996) reported that the metabolite, N-demethylated There was also a significant difference (p < 0.001) between the IC 50R/S for R-inhibiting S-zolmitriptan and the IC 50S/R for S-inhibiting R-zolmitriptan (Fig. 4).…”

Section: Concentrationmentioning

confidence: 85%

Determination of zolmitriptan enantiomers in rat liver microsomes by chiral high performance liquid chromatography with ?uorescence detection

Yao

et al. 2005

Biomed. Chromatogr.

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A selective chiral high performance liquid chromatographic method was developed and validated to separate and quantify the enantiomers of a new potent selective 5-HT(1B/1D) receptor partial agonist, S-zolmitriptan, and its antipode in rat liver microsomes induced with beta-naphtho flavone. S- and R-zolmitriptan were extracted from rat hepatic microsomal incubates with chloroform/isopropanol (75:25, v/v), and were separated on a narrow-bore enantioselective normal phase Chiralpak AD-H column (250 x 0.46 mm) with hexane-isopropanol-triethylamine (72/28/0.25, v/v/v) as mobile phase and fluorescence detection with emission at 350 nm and excitation at 291 nm. The calibration curves were linear for R- and S-zolmitriptan concentration over the range 0.1-5.0 microg/mL (r = 0.9996 and 0.9999), and the limits of quantitation were 0.1 microg/mL. The metabolism and interaction of the enantiomers of zolmitriptan in treated hepatic microsomes were investigated using chiral HPLC. There was significant difference between the disposition of the S- and R-zolmitriptan when racemic zolmitriptan or single enantiomers of zolmitriptan were incubated for 5, 10 and 20 min, suggesting that the metabolism of zolmitriptan in rat liver microsomes is enantioselective. In addition, there was also a significant difference between the IC(50) of R- to S-zolmitriptan and S- to R-zolmitriptan (IC(50S/R)/IC(50R/S) = 45.2). This indicated that the disposition process favored the S-form of zolmitriptan.

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Section: Concentrationmentioning

confidence: 85%

Determination of zolmitriptan enantiomers in rat liver microsomes by chiral high performance liquid chromatography with ?uorescence detection

Yao

et al. 2005

Biomed. Chromatogr.

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“…However, this dose is not clinically available or used in practice. 4,40 Finally, for all formulations, Zolmitriptan's elimination half-life is approximately 3 hours. 4,14,33 Pharmacokinetic differences in the ictal and interictal migraine periods…”

Section: Metabolism and Eliminationmentioning

confidence: 99%

A Review of the Pharmacokinetics, Pharmacodynamics and Efficacy of Zolmitriptan in the Acute Abortive Treatment of Migraine

Kalanuria

Peterlin

2009

Clinical Medicine. Therapeutics

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Migraine is a common and often disabling neurovascular disorder. Changes in the metabolism and the central processing of serotonin, as well as abnormalities in the modulation of the central and peripheral trigeminal nociceptive pathways, have been shown to play signifi cant roles in migraine pathophysiology. Recent evidence suggests that a low serotonin state facilitates activation of the trigeminal nociceptive pathways. In addition, several pharmacological agents that modulate serotonin are used in the treatment of migraine. Specifi cally there are seven FDA approved, 5-hydroxytryptamine (5-HT) 1B/1D receptor agonists, used for the acute abortive therapy of migraine. Zolmitriptan is one such triptan. Zolmitriptan is available as a tablet, orally disintegrating tablet and as a nasal spray. It is rapidly absorbed and detectable within the plasma, within 2 to 5 minutes for the nasal spray and within 15 minutes for the tablet. Zolmitriptan reaches peak plasma levels in 2-4 hours, with good levels maintained for up to 6 hours. Although the metabolism of zolmitriptan is predominantly hepatic, only 25% of zolmitriptan is bound to plasma proteins. Thus it is unlikely for drug interactions involving the displacement of highly protein-bound drugs. Zolmitriptan is very well tolerated with less than half of participants in clinical trials reporting adverse events, most of which were mild and transient. Although rare, serious cardiovascular events have been reported with all triptans. However, when patients are appropriately selected, zolmitriptan is both, a safe and effective acute migraine abortive agent. In this article, we will fi rst briefl y review the biological role of serotonin and the literature linking serotonin to migraine pathophysiology. This will be followed by a comprehensive review of the pharmacodynamics, pharmacokinetics and effi cacy of zolmitriptan. Finally, the clinical application of the use of zolmitriptan in migraine therapy will be discussed.

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“…Supine blood pressure, heart rate and blood sampling (for the determination of zolmitriptan and metabolites) were performed immediately before each test session. Plasma concentrations of zolmitriptan and its major metabolites were determined by reverse-phase high performance liquid chromatography with ßuorescence detection (Seaber et al 1996). Adverse experiences reported spontaneously and in response to an open question were recorded.…”

Section: Study Proceduresmentioning

confidence: 99%

“…Zolmitriptan also has a good pharmacokinetic proÞle, with rapid absorption following oral administration and dose proportional plasma concentrations (Seaber et al 1996). The absolute oral bioavailability is approximately 45 % and the half-life is 2.53 h.…”

Section: Introductionmentioning

confidence: 99%

“…At single doses of 2550 mg, much higher than the recommended therapeutic dose, zolmitriptan has been shown to cause sedation (Seaber et al 1996) Therefore a placebo-controlled study was conducted to investigate the e¤ects of zolmitriptan on psychometric task performance in healthy volunteers. The task battery was designed to investigate both objective and subjective drug e¤ects and all tests have previously been shown to be sensitive to the sedative e¤ects of lorazepam (Borland et al 1975;Hindmarch 1975).…”

Section: Introductionmentioning

confidence: 99%

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Lack of an effect of zolmitriptan (Zomig, 311C90) on psychometric task performance: results of a placebo-controlled study in healthy volunteers

Mercer

Lamb

Rolan³

et al. 1998

Psychopharmacology

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The novel selective 5-hydroxytryptamine (5-HT)1B/1D agonist, zolmitriptan (Zomig, formerly known as 311C90), has shown good efficacy in the acute oral treatment of migraine. Zolmitriptan acts both centrally and peripherally, therefore it is important to assess central nervous system effects. At single doses of 25-50 mg (up to 8 times the likely therapeutic dose), zolmitriptan can cause sedation; therefore, a study was designed to examine the dose-response. A double-blind, randomized, placebo-controlled, six-limb crossover study in 13 healthy volunteers compared the effects of single oral doses of zolmitriptan (5, 10, 15 or 20 mg) and lorazepam (2 mg) on various psychometric tests. Zolmitriptan doses less than 20 mg had no statistically significant effects on choice reaction time, the Stroop test, visual analog scale (VAS) assessments of physical sedation, tranquilization and other types of feelings, the logical reasoning test or the adaptive tracking test. There was a mild transient increase in the subjective assessment on VAS of mental sedation which was dose related and occurred mainly with the highest zolmitriptan dose and were not reflected in objective measures of drug effects. In contrast, lorazepam (used as a positive control) was associated with statistically significant impairment in all tests (except tranquilization) for up to 10 h after dosing. The results demonstrate that therapeutic doses of zolmitriptan are unlikely to cause clinically significant impairment in psychometric performance.

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The tolerability and pharmacokinetics of the novel antimigraine compound 311C90 in healthy male volunteers

Cited by 54 publications

References 7 publications

Determination of zolmitriptan enantiomers in rat liver microsomes by chiral high performance liquid chromatography with ?uorescence detection

Determination of zolmitriptan enantiomers in rat liver microsomes by chiral high performance liquid chromatography with ?uorescence detection

A Review of the Pharmacokinetics, Pharmacodynamics and Efficacy of Zolmitriptan in the Acute Abortive Treatment of Migraine

Lack of an effect of zolmitriptan (Zomig, 311C90) on psychometric task performance: results of a placebo-controlled study in healthy volunteers

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