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

Abstract

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.

Determination of zolmitriptan in human plasma by liquid chromatography–tandem mass spectrometry method: Application to a pharmacokinetic study

“…There was at most four-fold variability in AUC and C max between subjects, which is in agreement with published pharmacokinetic studies [7,8,10]. The plasma concentration-time curves were generally best fit by monoexponential decay, in which t 1/2 averaged 3.5 h. The mean AUC 0 → 24 h and AUC 0 → ∞ values were 55.6 and 56.2 ng h/ml, respectively.…”

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

“…39,41,42 The half-life (t 1/2 ) was unchanged between the genders. These differences are thought to be due to the reduced fi rst-pass metabolism of the drug in women.…”

“…Women show a higher mean C max and AUC values than men, (25.2 mg/L and 173.8 mg/L • h vs. 16 mg/L and 88.9 mg/L • h respectively) an observation, which is signifi cant only after a 5 mg dose and more pronounced with a 10 mg. 39 At doses greater than or equal to 5 mg, oral bioavailability of zolmitriptan has been shown to be greater in women than men. 39,41,42 The half-life (t 1/2 ) was unchanged between the genders.…”

“…58,43,[63][64][65] Uncontrolled hypertension, coronary artery disease, arrhythmias associated with accessory pathways such as Wolff-Parkinson-White syndrome, any condition associated with risk of stroke and concomitant use of MAO-A inhibitors, ergotamine or other 5-HT agonists use are considered contraindications to the use of zolmitriptan. 39 And like other triptans and ergots, there is concern with zolmitriptan about vasoconstriction. Although rare, triptan use has been associated with serious cardiovascular events, including myocardial infarction, stroke, and arrhythmia.…”

The pharmacokinetics of the antimigraine compound zolmitriptan in Japanese and Caucasian subjects

“…As gender differences had been noted in Western studies [11], a secondary objective was to compare the pharmacokinetics in male and female Japanese volunteers.…”