Flurbiprofen was rapidly absorbed in all species studied. 2. Half-lives of elimination measured 0 to 12 h after a single dose were: mouse 3.4 h, rat 2.5 h, dog 10.1 h, baboon 3.1 h and man 3.9 h. A second phase of elimination was seen in the dog. Flurbiprofen accumulated in the circulation of the dog on repeated dosing. 3. After dosing with [14C]flurbiprofen, tissue levels of radioactivity in dog and baboon were similar to that in plasma. In the rat, levels were slightly elevated in liver, kidney, large intestine and thyroid after repeated dosing. 4. The dog excreted equal amounts of radioactivity in urine and faeces. In other species renal excretion was the more important route. 5. Six metabolites have been detected, the most important being: 2-(2-fluoro-4'-hydroxy-4-biphenylyl)propionic acid (metabolite 1), 2-(i-fluoro-3',4'-dihydroxy-4-biphenylyl)propionic acid (metabolite 2) and 2-(2-fluoro-3'-hydroxy-4'-methoxy-4-biphenylyl)propionic acid (metabolite 3). The proportions of the metabolites and the extents of their conjugation varied among the species. 6. Metabolites were detected in the circulation of rat, mouse and baboon but not in dog and man. 7. Flurbiprofen did not affect the hepatic drug-metabolizing enzyme system of rat. 8. Flurbiprofen was extensively bound to serum protein of rat, dog, baboon and man.

The pharmacokinetic and haemodynamic effects of a 200 mg oral dose of BTS 49 465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were investigated in a double-blind placebo controlled study. BTS 49 465 was rapidly absorbed and cleared from the systemic circulation with a half-life of 1.6 h by oxidation to the sulphone metabolite. The metabolite was cleared with a half-life of 37.6 h. Saliva concentrations of both BTS 49 465 and its metabolite correlated well with the plasma concentrations. Compared to placebo, BTS 49 465 produced statistically significant reductions in blood pressure and increases in heart rate both supine and after a 60 degrees head up tilt. The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response. Plasma Renin Activity was only marginally elevated and there was no evidence of acute fluid retention. BTS 49 465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.

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A method has been developed for the separation and measurement of dothiepin and the N-desmethyl metabolite, northiaden, in human plasma or serum by high performance liquid chromatography. The method uses a structurally-related drug, amitriptyline, as an internal standard and provides a limit of detection of about 10 ng/ml for each component. At a concentration of 20 ng/ml, northiaden and dothiepin could be measured within ±11% and ± 6% of the mean respectively and at 200 ng/ml within ± 3% and ± 1% of the mean. The method has been applied to the analysis of serum from patients undergoing dothiepin therapy.

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