Abstract
The metabolism of two aromatic nitro chemotherapeutic agents has been investigated. One, 2-isopropylaminomethyl-6-methyl-7-nitro-1,2,3,4-tetrahydroquinoline (methamniquine) is a potent schistosomicide; the other 5,7-dinitroindazole possesses tuberculostatic activity. Methamniquine is oxidised in vervet and rhesus monkeys, dogs, rabbits, hamsters, rats and mice, to its 6-hydroxymethyl analogue (oxamniquine),a metabolite which shows a greater degree of schistosomicidal activity than the parent drug. Further oxidation at the 6-position occurs in all species to yield a carboxylic acid which is the major urinary metabolite in all species. When oxamniquine is administered to the same species and to man this same acid is again found as the major metabolite. Oxidation of the alkylaminoalkyl sidechain also occurred to a variable extent in all species studied to give a second carboxylic acid with the exception of the rat which oxidised the sidechain to an alcohol which was excreted in the bile as a glucuronide. The reason for this species difference in metabolism has been investigated and a possible biochemical mechanism is proposed. Reduction of these compounds was apparently not a significant route of metabolism. The urinary metabolites of dinitroindazole have been examined in mice and rats. The drug is extensively metabolised. Selective reduction of the 7-nitro group occurs in both species to give 5-nitro-7-aminoindazole as the major metabolite. Hydroxylation of the indazole ring also occurs to give 3-hydroxy-dinitroindazole, a minor metabolite in both species. A species difference is apparent in the further metabolism of 5-nitro-7-arainoindazole. In mice extensive N-glucuronidation is found, a synthesis not evident in the rat. In this species acetylation occurs to yield 5-nitro-7-acetamidoindazole. This metabolite is the probable precursor of two other metabolites in the rat. One of these has been positively identified as 3-hydroxy-5-nitro-7-acetamidoindazole. The other is suggested to be an N-hydroxylated derivative.