No abstract

Nimesulide is a preferential cyclo-oxygenase-2 inhibitory non-steroidal anti-inflammatory drug has, infrequently, been associated with hepatic reactions. To establish the extent of formation of various metabolites (some of which might be hepato-reactive) the whole body metabolism, plasma kinetics and routes of excretion of the radio-labelled drug was undertaken in 4 fasted male volunteers following an oral dose of 100 mg [ 14 C]-nimesulide. Urine, faecal and plasma samples were collected up to 168 h post dose, the total radioactivity and plasma concentrations of nimesulide and its principle metabolite, 4-hydroxynimesulide, were determined. Radio labelled metabolites in these samples was identified by combined liquid chromatography-mass spectrometry. The mean elimination half-life of total radioactivity in the plasma and whole blood was circa 4.8 h; the ratio whole blood and plasma being circa 0.6 h. The mean elimination half-lives for nimesulide and 4-hydroxynimesulide in plasma were circa 2.5 h and circa 3.9 h, respectively. The drug was rapidly excreted and recoveries were 59-66% in the urine and 33-39% in the faeces at 168 hours. A total of 16 metabolites were identified including the conjugated metabolites, which exceeds the 5 previously identified. Nimesulide was to be metabolised by 5 pathways involving (a) cleavage of the molecule at the ether linkage (b) reduction of the NO 2 group to NH 2 , and (c) ring hydroxylation followed by conjugation with either glucuronic acid or sulphate. In conclusion, the biotransformation pathway for nimesulide in man has now been comprehensively determined with 92% of the urinary metabolites fully characterised. The identification of some rare metabolites of nimesulide may help in understanding the mechanisms of hepatotoxicity from this drug.

No abstract

A large fraction of newly absorbed riboflavin is removed by the liver on "first pass." The plasma appearance method therefore underestimates riboflavin bioavailability and should not be used to estimate riboflavin bioavailability from foodstuffs. Urinary monitoring suggests that riboflavin from spinach is as bioavailable as is riboflavin from milk.

A route is described towards the pyrrolizidine † nucleus from derivatives of 5-acetylpyrrolidin-2-one using an intramolecular Wittig reaction with vinylphosphonium salts. The acetoxy ketone 15, derived from (S)-N-benzyloxycarbonylpyroglutamic acid, ‡ affords 16, a known precursor of (Ϫ)-supinidine.