Urinary metabolites of rifabutin, a new antimycobacterial agent, in human volunteers.

1. Metabolites of the antimycobacterial agent 4-deoxo-3,4-[2-spiro-(N-isobutyl-4-piperidyl)]-(1H)-imidazo-(2,5-dihydro )- rifamycin S (rifabutin) were isolated from human urine after administration of a single oral dose of the drug. Some of these metabolites were identified by direct inlet mass spectrometry, 1H-n.m.r. spectrometry and, in two cases, by chromatographic comparison with reference compounds. 2. Unchanged drug, 25-O-deacetyl rifabutin and four other metabolites were identified in human urine. 25-O-Deacetyl rifabutin was the main urinary metabolite, other metabolites were characterized as oxidized, and oxidized-deacetylated derivatives. 3. Routes of metabolic transformation were: (a) deacetylation at position 25, (b) oxidation of methyl groups 31 or 32 or at the piperidine nitrogen, and (c) combination of these.

Disposition and metabolism of [14-14C] 4-demethoxydaunorubicin HCl (idarubicin) and [14-14C]daunorubicin HCl in the rat. A comparative study.

The disposition of [14-14C]4-demethoxydaunorubicin HCl ([14-14C]idarubicin HCl, [14C]IDR) and of [14-14C]daunorubicin HCl ([14C]DNR) was studied in male Sprague Dawley rats. [14C]IDR was administered either IV at 0.25 mg/kg body weight or PO at 1 mg/kg body weight, whereas [14C]DNR was dosed IV at 1 mg/kg body weight. The main elimination route for both compounds was the bile, fecal excretion representing 0.75-0.8 times the total dose at 72 h. Radioactivity due to [14C]IDR-derived species is released by the tissues at a slower rate than activity derived from [14C]DNR. After IV treatment comparable plasma levels are obtained, but tissue radioactivity is markedly lower with [14C]IDR, in keeping with the lower dosage. The ratio of plasma to tissue radioactivity is even higher in animals treated PO with [14C]IDR, because of the more extensive metabolism after this route of administration. The 13-dihydro derivatives of both [14C]IDR and [14C]DNR are the main metabolites in tissues, but in the case of the former, products of phase II reactions become more important at later times in liver and kidney and in excreta.

Radioactive species in rat urines and tissues after [14C] AD 32 administration.

[14-14C]N-Trifluoroacetyldoxorubicin-14-valerate [( 14C]AD 32) was synthesized and administered IV to male rats at 9.09 mg/kg. Urinary radioactivity excreted in the 0-24 h interval was only 2.3% of the dose, N-trifluoroacetyldoxorubicin (AD 41), 13-dihydro-N-trifluoroacetyldoxorubicin (AD 92), and doxorubicin being the major urinary metabolites identified. Doxorubicin and AD 32 were the main radioactive species extracted from tissues at 24 h after treatment. The amount of doxorubicin present in the analysed tissue samples is in agreement with the relatively low toxicity of AD 32 compared with doxorubicin.

Disposition of 14C-labelled 4'-epidoxorubicin and doxorubicin in the rat. A comparative study.

The disposition of 4'-epi-[14-14C]doxorubicinHCl (4'-epi-[14C]DXR) and [14-14C]doxorubicinHCl [( 14C]DXR) was studied in male Sprague-Dawley rats given 1 mg/kg body weight IV. Most of the radioactivity administered was recovered in the faeces (two-thirds of the dose within 6 days after administration), urine accounting for 15% of the 14C given during the same period. A significant amount of radioactivity was also found in expired air. Significantly higher levels of radioactivity were recorded in the plasma (40 min and 4 h) and liver (40 min) in [14C]DXR-treated animals, whereas in animals treated with 4'-epi-[14C]DXR a higher specific radioactivity was found in the kidneys (40 min and 4 h) and bone marrow (40 min). The total tissue residual radioactivity was greater (P less than 0.05) at 24 h for [14C]DXR (45.8%) than for 4'-epi-[14C]DXR (38.6%). The main radioactive species in urines were the unchanged drugs. Minor metabolites were represented by a polar fraction, 13-dihydroderivatives, and aglycones. Whereas aglycones represent an important fraction of extractable tissue radioactivity in liver samples of many of the treated animals, the unchanged drug was invariably the major radioactive component in spleen, lung, and kidney. Liver extraction studies showed the presence of significant amounts of bound radioactivity that could be recovered in soluble form only after incubation with deoxyribonuclease. The main radioactive species present in the bile were the unchanged drug and a polar fraction. The amount of the former was higher in [14C]DXR-treated than in 4'-epi-[14C]DXR-treated animals. On the other hand, partial glucuronidation of 4'-epi-[14C]DXR was deduced on the basis of results of enzymic hydrolysis of bile samples.

Efectos del hidroxido de sodio en la pleura de la rata. / Effects of sodium hydroxide on the pleura of rats

Fueron instiladas dentro del espacio pleural de la rata normal 2 concentraciones de HONa, para observar la respuesta producida por este nuevo agente esclerosante.Se concluye que la injuria producida en la pleura de la rata por HONa produce un exudado pleural rico en proteinas y que la concentracion usada es un factor determinante para la produccion de sinfisis pleural que es progresiva con el transcurso del tiemp

Efectos del hidroxido de sodio en la pleura de la rata. / Effects of sodium hydroxide on the pleura of rats

Fueron instiladas dentro del espacio pleural de la rata normal 2 concentraciones de HONa, para observar la respuesta producida por este nuevo agente esclerosante.Se concluye que la injuria producida en la pleura de la rata por HONa produce un exudado pleural rico en proteinas y que la concentracion usada es un factor determinante para la produccion de sinfisis pleural que es progresiva con el transcurso del tiemp

Metabolism of metergoline in the rat.

[19,10-3H] Metergoline was administered orally to female rats and radioactive metabolites were recovered form urine and bile. Besides unchanged drug, the presence of 1-demethylmetergoline (II) was confirmed both in urine and bile. Two other urinary metabolites were identified, namely 8 beta-aminomethyl-6-methylergoline (IX) and 8 beta-acetylaminomethyl-6-methylergoline (VI). A third metabolite, 1,6-dimethyl-8 beta-aminomethylergoline (VIII), was identified only in bile. Beside these metabolites, further polar and so far unidentified biotransformation products are present both in bile and urine, accounting for about half of the radioactivity present in these excreta.

Radioisotopic and synthetic studies related to caroxazone metabolism in man.

Labelled 2-oxo-2H-1,3-benzoxazine-3(4H)-acetamide (caroxazone), has been synthesized by condensing N-(2-hydroxylbenzyl/glycinamide with 14C phosgene. Metabolic studies were performed administering the labelled drug to man and recovering metabolites from the urines. Beside the unchanged drug, five metabolites were identified and confirmed by synthesis, namely (3,4-dihydro-3-carboxamidomethyl-2-oxo-2H-1,3-benzoxazin-4-yl)urea (IX), N-carboxamidomethyl o-hydroxymethylphenyl carbamate (V), 4-methoxy-2-oxo-2H-1,3-benzoxazine-3(4H)acetamide (VIIIa), 2-oxo-2H-1,3-benzoxazine-3(4H)acetic acid (III) and 4-hydroxy-2-oxo-2H-1,3-benzoxazine-3(4H)acetamide (IV).