The clinical pharmacokinetics of zolmitriptan.

Zolmitriptan (Zomig, formerly 311C90) is a novel, oral, acute treatment for migraine. In healthy volunteers it is rapidly and extensively absorbed and has favorable oral bioavailability (approximately 40%) which is not affected by concomitant food intake. On average, 75% of its eventual Cmax is achieved within 1 h of dosing. Plasma concentrations are sustained for 4 to 6 h after dosing with single or multiple peaks in the plasma concentration-time profile, reflecting continued absorption down the gastrointestinal tract. The pharmacokinetics of zolmitriptan indicate dose proportionality over the dose range of 2.5 to 50 mg and there are no significant changes on multiple dosing. Zolmitriptan is cleared by metabolism followed by urinary excretion of the metabolites. There are three major metabolites, one of which, the N-desmethyl metabolite, is active as a 5HT1D agonist and has mean plasma concentrations approximately two thirds those of the parent compound. The other two metabolites, the N-oxide and indoleacetic acid, are inactive. The elimination half lives of zolmitriptan and its metabolites are similar, approximately 3 h. Zolmitriptan and its active metabolite are minimally protein bound in the plasma (approximately 25%). In migraine patients, plasma concentrations of zolmitriptan and its metabolites are lower during a migraine attack than outside an attack. In summary, the pharmacokinetics of zolmitriptan are simple, predictable and appropriate to an acute oral treatment for migraine.

The disposition of tert-butyl-D-serine in the rat.

1. Following intravenous administration of 14C-tert-butyl-D-serine to rats, radioactivity was eliminated rapidly via the kidneys. 2. One metabolite was detected in urine and was identified as the N-acetyl derivative of tert-butyl-serine. 3. Elimination was more rapid in female than male rats.

Sulphation and glucuronidation of xamoterol in the dog: dose dependence and site of sulphation.

1. Xamoterol has been administered both intravenously and orally over a 100-fold dose range to male beagle dogs. 2. Over the dose range examined, sulphation was not saturable, with the proportion of the dose excreted as the sulphate conjugate remaining constant. 3. Extensive first-pass sulphation of an oral dose of xamoterol occurred in the intestine with approximately 50% of sulphation occurring during absorption. 4. The intestine is not a major site of sulphation for circulating xamoterol. 5. The liver is not believed to play an important role in the first-pass sulphation of xamoterol.

Incorporation of radiolabelled amino acids into the sulphur-containing metabolites of paracetamol by the hamster.

Various radiolabelled forms of the amino acids cysteine, methionine and serine were co-administered with paracetamol to the hamster to investigate the biosynthesis of the thiomethyl metabolites of paracetamol. T.l.c. and h.p.l.c. were used to determine the presence of sulphur-containing metabolites in the urine. Paracetamol sulphate and the 3-cysteine, mercapturate and thiomethyl derivatives were all detected in urine, along with the 3-methylsulphoxide after hydrolysis. No paracetamol-3-methylsulphone was detected. Both cysteine and methionine acted as sulphur donors via glutathione. The methyl group of the thiomethyl derivatives originated from methionine in a reaction system believed to involve cysteine conjugate-beta-lyase and the thiomethyl shunt.

The disposition and metabolism of 5-(4,5-dihydro-2-phenylbenz[e]indol-3-yl)salicylic acid (fendosal) in the rat, mouse, rabbit, do, rhesus monkey, and man.

The disposition and metabolism of 5-(4,5-dihydro-2-phenylbenz[e]indol-3-yl)salicylic acid (fendosal) a new salicylate-type analgesic, has been studied in the rat, mouse, rabbit, dog, rhesus monkey, and man. Animals were given single oral or parenteral doses at levels of 5, 10, or 50 mg/kg; human volunteers received 200 mg orally. In all species, virtually all radioactivity was excreted in the feces. Biliary excretion accounted for approximately 50% of an oral dose in the rat and dog. Enterohepatic circulation was demonstrated in the rat. The compound was fairly rapidly absorbed in all species except the rhesus monkey. The principal excretion products found in all species were unchanged fendosal and a monohydroxylated metabolite, the latter being present both in the free state and as a glucuronide. A minor metabolite, present only in man and rhesus monkey, was tentatively identified as a dihydroxylated metabolite. These compounds were, however, detected only in unpurified samples. During the isolation and purification procedure, oxidation occurred, resulting in the production of the corresponding dehydrogenated derivatives, which were the actual materials whose structures were elucidated.

An improved method for gas chromatographic determination of urinary xylitol and glucuronic, glucaric gulonic and ascorbic acids, with their values in the rat, rabbit, guinea-pig and marmoset.

1. Urinary levels of xylitol and glucuronic, glucaric, gulonic and ascorbic acids were measured in the rat, rabbit, guinea-pig and marmoset by an improved g.l.c. technique. 2. Administration of a compound (2-methylbenzanilide) known to be conjugated and excreted as a beta-glucuronide had some effect on the output of these compounds of the glucuronic acid pathway in all four species, and caused a significant decrease in gulonic acid in the rat.