The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90).
OBJECTIVE
Two open studies in healthy volunteers were conducted to determine the absolute bioavailability and metabolic disposition of zolmitriptan (311C90), a novel 5HT1D agonist for the acute treatment of migraine.


METHODS
After an initial test i.v. infusion, bioavailability 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 microCi [14C]-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 i.v. 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, Cmax 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, V2 and t1/2,z after i.v. dosing (all subjects) were 8.7 +/- 1.7 ml min-1 kg-1, 122 +/- 321 and 2.30 +/- 0.59 h respectively. Following administration of 25 mg [14C]-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 [14C] 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 metabolites 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 bioavailability for an acute oral migraine treatment and there are no significant unidentified metabolites in man.
Seaber
E
E
Division of Clinical Pharmacology, Glaxo Wellcome Research and Development, Greenford, Middlesex, UK.
On
N
N
Dixon
R M
RM
Gibbens
M
M
Leavens
W J
WJ
Liptrot
J
J
Chittick
G
G
Posner
J
J
Rolan
P E
PE
Pack
R W
RW
D000042:Absorption; D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D006801:Humans; D007210:Indoleacetic Acids / Q000378:metabolism; D007262:Infusions, Intravenous; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy; D010080:Oxazoles / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D023303:Oxazolidinones; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D012737:Sex Factors; D014363:Tryptamines
D007210:Indoleacetic Acids; D010080:Oxazoles; D023303:Oxazolidinones; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan