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.

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.

3 fi, 10-HJMetergoline (9) has been prepared starting from 1-methyllysergamide (5) which was reduced with tritium gas to 1-methyl-fi, 1 0-3H]dihydrolysergamide. ted to 2 in two steps with a 42% overall radiochemical yield.[ G 3 H ] and 6 7 -HJnicergoline were prepared starting from generally labelled fi and from 2 respectively. The latter was obtained by reducing the ester (13) with sodium borol3H2hydride. Similarly, l-demethyl-fi7-HJnicergoline (=) was also obtained. & m b~l -~~C 2 5-bromonicotinic acid (2) was prepared from K14CN y & 3-L-l 4CJcyanopyridine (16) which was converted into 17 and Einally brominated. nicergoline (z) was obtained by condensation of 2 and 2.Radiochemical yield of l5, 1 & , and 15b from 3 and was approximately 4osC after the chromatographic purification step.

SUMMARYTwo syntheses of radiolabelled spiro-piperidyl-rifamycins are described.

The synthesis of 4' -iodo-4 l -[ 14-l4C1 -deoxydoxorubicin hydrochloride (PCE 21954) in five steps is described. 4 -Epi-N-trif luoroacetyl-[ 14-14C] -daunorubicin has been employed as starting material. substitution of C-4l-OH with iodine and subsequent hydroxylation of the side chain, via the 14-bromo derivative, of 41-iodo-41 -[ 14-14Cl-deoxydaunorubicin afforded the final product, in an overall radiochemical yield of 20%, 96% radiochemically pure and with a specific radioactivity of 252 MBq/mol (6.8 mCi/mmol).