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Titolo:
THE ABSOLUTE BIOAVAILABILITY AND METABOLIC DISPOSITION OF THE NOVEL ANTIMIGRAINE COMPOUND ZOLMITRIPTAN (311C90)
Autore:
SEABER E; ON N; DIXON RM; GIBBENS M; LEAVENS WJ; LIPTROT J; CHITTICK G; POSNER J; ROLAN PE; PECK RW;
Indirizzi:
GLAXO GRP RES LTD,DIV CLIN PHARMACOL,GREENFORD RD GREENFORD UB6 0HE MIDDX ENGLAND
Titolo Testata:
British journal of clinical pharmacology
fascicolo: 6, volume: 43, anno: 1997,
pagine: 579 - 587
SICI:
0306-5251(1997)43:6<579:TABAMD>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
SUMATRIPTAN; PHARMACOKINETICS; DRUG;
Keywords:
BIOAVAILABILITY; METABOLISM; 311C90; ZOLMITRIPTAN; RADIOLABEL; PHARMACOKINETICS; GENDER;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
13
Recensione:
Indirizzi per estratti:
Citazione:
E. Seaber et al., "THE ABSOLUTE BIOAVAILABILITY AND METABOLIC DISPOSITION OF THE NOVEL ANTIMIGRAINE COMPOUND ZOLMITRIPTAN (311C90)", British journal of clinical pharmacology, 43(6), 1997, pp. 579-587

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 mu Ci [C-14]-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, consistentwith 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 zolmitriptan concentrations, metabolite concentrations were higher after oral dosing than after i.v., and higher in men compared with women. Half-lifewas 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 +/- 321 and 2.30 +/- 0.59 h respectively. Following administration of 25 mg [C-14]-zolmitriptan, 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 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 [C-14] 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% ofthe 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/11/20 alle ore 15:56:59