EFFECT OF SUBSTITUENTS ON THE METABOLISM OF NITRACRINE IN RAT

1. Male Wistar rats were treated with either the antitumour agent nitr acrine -nitro-9-(3'-dimethylamino-N-propylamino)-acridine ; NC), 4-met hoxy-NC, NC-aliphatic-N-oxide, 4-methoxy-NC-aliphatic-N-oxide, or NC-a romatic N-oxide (30 mu mol/kg, via the femoral vein) and the major bil iary and urinary metabolites analysed by hplc. 2. No NC or 4-methoxy-N C were detected in bile or urine of rat treated with NC or 4-methoxy-N C respectively, whereas the aliphatic N-oxides of NC and 4-methoxy-NC were recovered largely unchanged in both bile and urine. 3. NC-aromati c-N-oxide was rapidly and extensively converted to a major polar bilia ry product. This product was also synthesised enzymatically from NC-ar omatic-N-oxide using rat liver cytosol and has been identified by mass and H-1-nmr spectrometry as dimethylamino-N-propylamino)-acridine-N(1 0)-oxide. 4. The equivalent 1-(S-glutathionyl) conjugate appears to be formed from NC, and excreted in bile as a minor product, but not from 4-methoxy-NC. Further experiments with cytosol indicate that direct d isplacement of the nitro group by GSH is mediated by GSH transferase. 5. Finally, the major biliary metabolite of NC has been provisionally identified as a glucuronide of 1-nitro-2-hydroxy-NC. 6. It is conclude d that, for at least a significant fraction of NC, nitroreduction does not occur. Further, N-oxidation of the aliphatic (but not the aromati c ring) nitrogen, plus 4-methoxy substitution, decreases the overall m etabolism of NC in the rat.