N-oxidation of N,N-dimethylaniline in the rabbit and rat lung

We have reported previously that chlorpromazine (CPZ) and imipramine (IMP) are metabolized via N-oxidation by the rat lung, while they are not appreciably metabolized by the rabbit lung. Indeed, marked species differences exist in the pulmonary N-oxidation of these pneumophilic drugs. In the present studies, the isolated, ventilated and perfused lung (IPL) preparations as well as in vitro preparations of the rabbit and rat lungs were used to examine the pulmonary disposition of [14C]-N,N-dimethylaniline (DMA) which has been used frequently as a substrate for N-oxidation. Although the IPLs of both species were active in DMA N-oxidation, the rabbit lung was more active in DMA N-oxidation than the rat lung on the basis of per g lung. The gradual decline in radiolabel concentration in the perfusate was more marked in the rat than in the rabbit IPL. This decline was not due to the drug accumulation in the lung, but to its volatility. There was no dose dependency in the tissue/medium DMA concentration ratios (approximately 1.60), indicating uptake by simple diffusion and low affinity for the lung tissue. In vitro lung preparations showed higher DMA N-oxidase activity in the rabbit than in the rat, regardless of whether whole homogenate, post-mitochondrial supernatant fraction or microsomal fraction was used, or how the activities were expressed (per mg protein or per g tissue). These results suggest that, although DMA is not highly concentrated in the lung, it is N-oxidized by the lung and that DMA N-oxidase is different from CPZ or IMP N-oxidase reported previously.