Effect of substituents on the metabolism of nitracrine in rat

Abstract

1. Male Wistar rats were treated with either the antitumour agent nitracrine (1-nitro-9-(3'-dimethylamino-N-propylamino)-acridine; NC), 4-methoxy-NC, NC-aliphatic-N-oxide, 4-methoxy-NC-aliphatic-N-oxide, or NC-aromatic-N-oxide (30 μmol/kg, via the femoral vein) and the major biliary and urinary metabolites analysed by hplc.

2. No NC or 4-methoxy-NC were detected in bile or urine of rat treated with NC or 4-methoxy-NC respectively, whereas the aliphatic N-oxides of NC and 4-methoxy-NC were recovered largely unchanged in both bile and urine.

3. NC-aromatic-N-oxide was rapidly and extensively converted to a major polar biliary product. This product was also synthesised enzymatically from NC-aromatic-N-oxide using rat liver cytosol and has been identified by mass and ¹H-nmr spectrometry as 1-(S-glutathionyl)-9-(3'-dimethylamino-N-propylamino)-acridine -N(10)-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 displacement 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 concluded that, for at least a significant fraction of NC, nitroreduction does not occur. Further, N-oxidation of the aliphatic (but not the aromatic ring) nitrogen, plus 4-methoxy substitution, decreases the overall metabolism of NC in the rat.