Pulmonary Metabolism of Imipramine in the Rat and Rabbit

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Abstract
The pulmonary metabolism of imipramine (IMP) was studied, using lung tissue preparations of rats and rabbits, and compared with the metabolism by liver tissue. The postmitochondrial (9,000 g) supernatant fraction was used as the enzyme source, and the differential extraction method was employed to separate and quantitate the metabolites of IMP. The IMP-metabolizing activity of rat lung was found to be significantly higher than that of rabbit lung. The major metabolite produced by rat lung was identified as IMP-N-oxide (IMP-NO). Inclusion of β-dimethylaminoethyl-diphenyl valerate (SKF-525A; 1 mM) and depletion of Mg2+ did not inhibit, but slightly increased the N-oxidation of IMP by the lung preparations, whereas piperonyl butoxide (1 mM) and Hg2+ (0.1 mM) had little or no effect. The liver/lung ratio of the IMP-metabolizing activity was found to be variable depending on the substrate concentrations used, indicating the unreliability of such ratios as indices of the relative contribution of the lung to the metabolism of a drug. These results suggest that a marked species variation exists with respect to the pulmonary metabolism of IMP, that the principal product in rat lung is IMP-NO, and that this biotransformation is catalyzed by a noncytochrome P-450 pathway.