Richard C. Cottrell

Studies of the urinary metabolites of N-nitrosopyrrolidine in the rat.

Abstract The urinary excretion of radioactive metabolites following the ip administration of a range of doses of N -nitroso[2,5- 14 C]pyrrolidine was examined. Several metabolites were identified: pyrrolidinone-2-oxime, pyrrolidin-2-one, γ-hydroxybutyric acid, γ-butyrolactone, succinic semialdehyde, 3-hydroxy- N -nitrosopyrrolidine, dimethylamine and urea and their 3 H: 14 C ratio determined following the administration of N -nitroso[2,2,5,5- 3 H; 2,5- 14 C]pyrrolidine. The effect of pretreatment with inhibitors and an inducer of the cytochrome P -450 system and of a number of compounds, which inhibit the in vivo metabolism of N -nitrosopyrrolidine, on the urinary excretion of a number of metabolites was examined. The results are considered in terms of the possible metabolic processes that may be involved in N -nitrosopyrrolidine biodegradation.

Studies of the metabolism of N-nitrosopyrrolidine in the rat.

The effect of pretreatment with SKF 525A, piperonyl butoxide, Aroclor 1254, disulfiram, iminazole, pyrazole, 3-methylpyrazole, or tranylcypromine on the rate of metabolism of N-nitroso[2,5-14C]pyrrolidine to 14CO2 was examined in the rat. The effectors of the liver microsomal mixed-function oxidase system, SKF 525A, piperonyl butoxide, and Aroclor 1254, showed no significant effect on the rate of 14CO2 exhalation. Disulfiram, pyrazole, and iminazole, however, showed a prolonged inhibition of metabolism which was still apparent 6 hr after the administration of these compounds. 3-Methylpyrazole and tranylcypromine produced a more transient inhibitory effect. The metabolism of nitrosopyrrolidine in the isolated perfused liver was observed to be very much slower than that observed in vivo, suggesting a role for at least one other organ in the biodegradation of this nitrosamine. Evidence is presented which suggests that the small intestine may be one extrahepatic site of metabolism. These results are compared with those previously obtained for N-nitrosodimethylamine.