THE ABSOLUTE BIOAVAILABILITY AND METABOLIC DISPOSITION OF THE NOVEL ANTIMIGRAINE COMPOUND ZOLMITRIPTAN (311C90)

Aims Two open studies in healthy volunteers were conducted to determin e the absolute bioavailability and metabolic disposition of zolmitript an (311C90), a novel 5HT(1D) agonist for the acute treatment of migrai ne. Methods After an initial test i.v. infusion, bioavailabilty was as sessed by comparison of AUC after an i.v. infusion (3.5 mg) and an ora l tablet (10 mg), in six men and six women using a randomised, crossov er design. Disposition was studied by administration of a 25 mg capsul e, labelled with 100 mu Ci [C-14]-zolmitriptan, to five men and one wo man on a single occasion. Results Zolmitriptan was well tolerated by b oth 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,, and AUC values in women were approximately double those in men. Relative to zolmitripta n concentrations, metabolite concentrations were higher after oral dos ing 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%). M ean +/- s.d. values for CL, V-z and t(1/2,z) after i.v. dosing (all su bjects) were 8.7 +/- 1.7 ml min(-1) kg(-1), 122 +/- 321 and 2.30 +/- 0 .59 h respectively. Following administration of 25 mg [C-14]-zolmitrip tan, 91.5% of the dose was recovered in 7 days, 64.4 +/- 6.5% in urine and 27.1 +/- 16.0% in faeces. Less than 10% was recovered unchanged i n urine, with 31.1 +/- 6.4% recovered as the inactive indole acetic ac id metabolite. Most of the faecal material was unchanged zolmitriptan, representing unabsorbed drug. Plasma concentrations of [C-14] were sl ightly higher than those of the summed concentrations of known analyte s zolmitriptan, the active N-desmethyl metabolite (183C91), the inacti ve N-oxide (1652W92) and indole acetic acid (2161W92) metabolites, whi ch accounted for 86% of total plasma radioactivity. No other significa nt metabilites were detected in plasma. Some minor additional metaboli tes were detected in urine, none of which contributed more than 5% of the dose. Conclusions The data suggest that zolmitriptan undergoes fir st-pass metabolism and this is more extensive in men than in women. Zo lmitriptan has suitable bioavailabilty for an acute oral migraine trea tment and there are no significant unidentified metabolites in man.