Studies of the metabolism of N-methyl containing anti-tumour agents : 14CO 2 breath analysis after administration of 4C-Labelled N-methyl drugs, formaldehyde and formate in mice

Abstract

The 14CO 2; content of the breath was analysed after administration of the following N- 14 CH 3 labelled drugs to mice: aminopyrine, hexamethylmelamine (HMM), pentamethylmelamine (PMM), procarbazine and caffeine. Except for aminopyrine, the 14CO 2; exhalation rate plots declined monophasically with half lives of 91 min ([ 14C]-HMM), 97 min ([ 14C]-PMM), 68 min ([ 14C]procarbazine) and 92 min ([ 14C]caffeine). The 14CO 2 exhalation rate peaked rapidly after aminopyrine administration and declined bi-phasically with an initial t 1 2 of 15 min and a terminal t 1 2 of 126 min. The 14CO 2; plots after both [ 14C]-HMM and [ 14C]aminopyrine were influenced by pre-treatment of mice with proadifen. Pretreatment with phenobarbitone shortened the t 1 2 of the 14CO 2 appearance rate after [ 14C]HMM by 24% but did not change the 14CO 2 curve after administration of [ 14C] aminopyrine. The 14CO 2 exhalation rate plots after administration of H 14CHO and H 14COOH were virtually identical with that obtained after [ 14C]aminopyrine and not influenced by either proadifen or phenobarbitone pretreatment. The 14CO 2 exhalation rate profile obtained on metabolism of [ 14C]aminopyrine in mice thus appears to be determined by the rate of the oxidation of formaldehyde or formate to CO 2. Only 24% of the label injected with the N-methyl moieties of [ 14C]HMM and 21% of the label in [ 14C]procarbazine were exhaled as 14CO 2, whereas 49% of the N- 14CH 3 in [ 14C]aminopyrine were metabolized to 14CO 2. It remains to be determined whether this difference and the difference in the shapes of the 14CO 2 exhalation profiles obtained with the cytotoxic N- 14CH 3 drugs as compared to [ 14C]aminopyrine, are related to the biochemical processes mediating their antineoplastic activity.