14C-Rifabutin was given orally to rats, rabbits and monkeys at a dose of 25 mg/kg and to healthy volunteers at a dose of 270 mg. Radioactivity was eliminated by both the renal and faecal routes in all species, with a predominance of the renal route in man and monkeys (50.19% and 46.73% of the dose, respectively, in urine at 96 h), whereas in rats and rabbits a slight predominance of faecal excretion was observed (48.09% and 45.01% of the dose, respectively, at 96 h in faeces; 42.22% and 36.37% in urine). Radioactivity as expired 14CO2 was detected in the rat and accounted for less than 0.5% of the dose within 96 h. The drug was rapidly absorbed and peak plasma radioactivity levels were reached from 1 to 4 h after dosing. Rifabutin was the predominant compound circulating in plasma at the first sampling times, but significant levels of 31-OH rifabutin were detected up to 8-24 h in all species studied. 25-O-deacetyl rifabutin was detected only in rat and man. Polar metabolites were also present, particularly at the later sampling times. The urinary metabolism was studied by radio-HPLC. Rifabutin accounted for 8.5% and 4.6% of the dose in 0-24 h urine of rats and man respectively, whereas in rabbit and monkey urine only traces of this compound were detected. The main known metabolite in all animal species was 31-OH rifabutin; 25-O-deacetyl rifabutin was detected only in rat and man. The remaining urinary radioactivity was mainly due to polar compounds.

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.

'4C-rifabutin was given orally (25 mg/kg) and intravenously (i.v.) (10 mg/kg) to female Sprague-Dawley rats.Radioactivity was eliminated by both the renal and fecal routes, amounting to 44.49 and 43.39% of the dose, respectively, in urine and feces at 96 h after the oral dose and to 47.81 and 40.76% of the dose, respectively, in urine and feces after the i.v. dose. Differences between the two routes of administration were negligible. Tissue distribution of radioactivity after the oral dose was investigated by the combustion technique. At 2 h, the highest concentration of radioactivity was observed in the liver, followed by the lung, abdominal adipose tissue, and spleen, whereas at 72 h, the sequence was abdominal adipose tissue, liver, spleen, bone marrow, and lung. Brain levels of radioactivity were very low. The results of whole-body autoradiography after i.v. administration confirmed the above. Whole-body autoradiography of pregnant rats showed higher concentrations of radioactivity in the uterus than in the placenta and trace levels in the fetuses up to 8 h. Radioactivity was absent in the amniotic fluid. The urinary metabolism was studied by radio-high-pressure liquid chromatography. Rifabutin accounted for 7.4 and 7.2% of the dose in 0-to 48-h urine after oral and i.v. administration, respectively. Metabolites 31-OH rifabutin and 25-O-deacetyl rifabutin amounted to 4.3 and 1.6% of the dose, respectively, after oral administration and to 2.6 and 0.7% of the dose, respectively, after i.v. administration. The remaining urinary radioactivity was mainly due to polar compounds. Fig. 1), is a new spiropiperidylrifamycin with a broad spectrum of activity against typical and atypical gram-positive and gram-negative bacteria in vitro (6). The drug is also active against many rifampin-resistant Mycobacterium tuberculosis strains both in vitro and in vivo (6, 11).A comparative study of the absorption, elimination, and metabolic pattern in some animals and humans after oral administration of the labeled drug has been previously reported (2). The aim of the present study was to further investigate the absorption, disposition, and urinary metabolism of 14C-rifabutin in rats following oral and intravenous (i.v.) administration.As the chemical structure of rifabutin is similar to that of rifampin, a drug currently used in the treatment of tuberculosis, but its lipophilicity is much higher (3), it was considered interesting to compare data obtained in this study with those reported in the literature for labeled rifampin. MATERIALS AND METHODSChemicals. 14C-rifabutin (Fig. 1), with a specific activity of 1.50 MBq/mg and a radiochemical purity higher than 97% by thin-layer chromatography, was synthesized in the Radioiso- 160 and 215 g) and three pregnant (on day 16 of gestation) female Sprague-Dawley rats were used in this study. The animals were fasted overnight and up to 4 h after dosing. Water was available ad libitum. Animals were housed individually in cages suitable for separate collection of urine and feces.Absorption,...

A gas chromatographic method is described that is suitable for the determination of benalaxyl residues ranging from 10 to 0.1 μg/kg in several crops, must, wine, and water. The compound is extracted with acetone and purified either by partitioning between water and n-hexane or by passing the extract through an Extrelut column with n-hexane. Further purification is achieved by column chromatography on alumina. The active ingredient is finally determined by gas chromatography with nitrogenphosphorus detection. Mean recoveries were ≥95% in the various crops tested and in the 0.01-1.05 mg/kg fortification range. Standard deviations for each crop were ≤6.5%.

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.