ABSTRACT
The synthesis and antiinflammatory activity of 2-amino-3-benzoylphenylacetic acid are described. This compound was postulated to be an active metabolite of 7-benzoylindoline in order to explain the unexpected antiinflammatory activity of the latter compound. Metabolism studies on 14C-labeled 7-benzoylindoline did not confirm this hypothesis. Nevertheless, 2-amino-3-benzoylphenylacetic acid, its ethyl ester, and the sodium salt show potent antiinflammatory activity in pharmacological models.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Phenylacetates/chemical synthesis , Animals , Arthritis, Experimental/drug therapy , Benzophenones/chemical synthesis , Benzophenones/metabolism , Benzophenones/pharmacology , Benzophenones/therapeutic use , Biotransformation , Female , In Vitro Techniques , Male , Phenylacetates/metabolism , Phenylacetates/pharmacology , Phenylacetates/therapeutic use , Pleural Effusion/drug therapy , RatsABSTRACT
1. Following an oral dose of S-carboxymethyl [35S]cysteine monkey (rhesus and African green), rat, dog, and man excreted 77,88,95, and 100% respectively of the 35S radioactivity in urine and 7.0, 2.5, 0.7, and 0.3% in faeces during a 3 to 4 day period. 2. The principal drug-related components excreted were unchanged carboxymethylcysteine, dicarboxymethyl sulphide and inorganic sulphate. 3. Rat, dog, and man excreted primarily dicarboxymethyl sulphide and unchanged carboxymethylcysteine and no inorganic sulphate (rat, 7%). 4. Monkey excreted largely inorganic sulphate, moderate amounts of dicarboxymethyl sulphide and a trace of unchanged drug.
Subject(s)
Carbocysteine/metabolism , Cysteine/analogs & derivatives , Animals , Biotransformation , Carbocysteine/blood , Carbocysteine/urine , Chromatography, High Pressure Liquid , Dogs , Feces/analysis , Female , Haplorhini , Humans , Macaca mulatta , Male , Rats , Species Specificity , Time FactorsABSTRACT
Studies with a 14C-labeled sample have shown that the title compound A is readily absorbed and very rapidly excreted by the rat, dog, and man. The metabolites result from aromatic ring hydroxylation, oxidation, and dealkylation of the urea methyl group, and oxidative ring opening of the pyrrolidine ring. Rat metabolites were 3-(3-chloro-4-hydroxyphenoxy)-N-methyl-l-pyrrolidinecarboxamide (C) 3-(3-chloro-4-hydroxyphenoxy)-1-pyrrolidinecarboxamide (D), 3-(3-chlorohydroxyphenoxy)-1-pyrrolidinecarboxamide (E), 3-(3-chlorophenoxy)-4([(methylamino)-carbonyl]amino)butanoic acid (G), 3-(3-chlorophenoxy)-4[(aminocarbonyl)amino]butanoic acid (H). Dog metabolites were C, D, G, and H. Human metabolites were 3-(3-chloro-4-hydroxyphenoxy)-N-formyl-l-pyrrolidinecarboxamide (F), C, D, G, and H. An electron-capture gas chromatographic assay for the parent compound is described. Whole-body autoradiograms of rat slices and the tissue residue data from these slices are reported and indicate rapid tissue depletion of radioactivity.
Subject(s)
Pyrrolidines/metabolism , Animals , Carbamates/blood , Carbamates/metabolism , Carbamates/urine , Chromatography, Gas , Chromatography, Thin Layer , Dogs , Glucuronates/urine , Humans , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Organ Specificity , Pyrrolidines/blood , Pyrrolidines/urine , Rats , Species Specificity , Spectrophotometry, Ultraviolet , Structure-Activity Relationship , Time FactorsABSTRACT
Bethanidine is metabolized in the rat and dog to a significant degree to N-benzyl-N'-methylguanidine, N-benzylguanidine, N-hydroxybenzyl-N'-methylguanidine, N-methylguanidine, N-hydroxybenzyl-N',N''-di-methylguanidine, and benzoic acid, whereas in man the drug is not metabolized. It is readily absorbed in all three species. The elimination kinetics in man show a difference between the urinary excretion rate and the rate of decline in the blood. Whole body autoradiograms showed a high concentration of drug in rat tissues rich in adrenergic nerve terminals, but insignificant penetration, if any, of the blood-brain barrier.
