Radioimmunological determination of fenoterol. Part II: Antiserum and tracer for the determination of fenoterol.

A radioimmunological method for the determination of the concentration of fenoterol in biological samples is described. The mixture of antibodies against the enantiomers of fenoterol obtained with the selected hapten shows a high affinity for racemic fenoterol and for the monoiodo125-fenoterol used as a tracer, which is also present as a racemate. The limit of detection of the radioimmunoassay for fenoterol (racemate) in biological samples (plasma, urine) is 10-20 pg/ml. The precision and accuracy of the radioimmunoassay, in the presence of racemic fenoterol, are sufficient for an analysis and meaningful interpretation of samples from human pharmacokinetic studies. A relationship between the cross-reactivity of the antibodies against fenoterol and a preferred conformation of the fenoterol molecule in aqueous solution is discussed.

Synthesis of the bronchospasmolytic agent flutropium bromide and of some homologous and configuration isomeric compounds.

A technically practicable synthesis of unknown N-beta-fluoroalkyl-substituted benzilic acid nortropine esters, among them (8r)-8-(2-fluoroethyl)-3 alpha-hydroxy-1 alpha H, 5 alpha H-tropanium bromide benzilic acid ester (flutropium bromide, Ba 598 BR), and their configuration isomeric quaternary salts via benzilic acid imidazolide is described. The quaternization which takes place with sufficiently high stereo-selectivity leads to configuration isomers which differ not only in their physico-chemical properties but also in their profile of pharmacological action.

Blood level, distribution, excretion, and metabolite pattern of [14C]-brotizolam in the rat, dog, and rhesus monkey.

Following oral and intravenous administration the absorption, distribution, metabolite pattern and excretion of 14C-labeled brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-1,2,4-triazolo [4,3-a]-1,4-diazepine, We 941, Lendormin), a new hypnotic, was studied in rats, dogs, and rhesus monkeys. Given orally to these species, [14C]-brotizolam was rapidly and extensively absorbed. The distribution of the radiolabeled drug was very fast indicated by blood level curves as well as by rat whole body autoradiography. [14C]-Brotizolam and its metabolites crossed the placenta; they also occurred in the milk of rats. In all species studied radioactivity was eliminated from blood with very similar half-lives ranging from 14.8 to 20.8 h. The renal portion of the total radioactivity elimination increased from 5.5% of the dose given to rats to 33.5% in rhesus monkeys and to 51.4% in dogs. Total excretion was complete 3 to 4 days after [14C]-brotizolam administration. Biliary excretion also occurred. In the species studied thin layer chromatographic separation of the biliarily and renally excreted radioactivity indicated a similar but not the same pattern of 2 to 3 major metabolites which were mostly totally conjugated. Unchanged [14C]-brotizolam was only excreted in minor quantities, if at all.